1,966
Views
0
CrossRef citations to date
0
Altmetric
Review

Immunotherapy resistance in solid tumors: mechanisms and potential solutions

ORCID Icon, ORCID Icon & ORCID Icon
Article: 2315655 | Received 24 Jul 2023, Accepted 04 Feb 2024, Published online: 22 Feb 2024

References

  • Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: From t cell basic science to clinical practice. Nat Rev Immunol. 2020;20(11):651–17. doi:10.1038/s41577-020-0306-5.
  • de Miguel M, Umana P, Gomes de Morais AL, Moreno V, Calvo E. T-cell–engaging therapy for solid tumors. Clinical Cancer Research. 2021;27(6):1595–1603. doi:10.1158/1078-0432.CCR-20-2448.
  • Nathan P, Hassel JC, Rutkowski P, Baurain J-F, Butler MO, Schlaak M, Sullivan RJ, Ochsenreither S, Dummer R, Kirkwood JM, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385(13):1196–1206. doi:10.1056/NEJMoa2103485.
  • Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. 2015;15(6):388–400. doi:10.1038/nri3839.
  • Fu Q, Fu TM, Cruz AC, Sengupta P, Thomas SK, Wang S, Siegel RM, Wu H, Chou JJ. Structural basis and functional role of intramembrane trimerization of the fas/cd95 death receptor. Mol Cell. 2016;61(4):602–613. doi:10.1016/j.molcel.2016.01.009.
  • Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118(1):9–16. doi:10.1038/bjc.2017.434.
  • Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: Insights into tumour immunogenicity and immune evasion. Nat Rev Cancer. 2021;21(5):298–312. doi:10.1038/s41568-021-00339-z.
  • Kaklamanis L, Townsend A, Doussis-Anagnostopoulou IA, Mortensen N, Harris AL, Gatter KC. Loss of major histocompatibility complex-encoded transporter associated with antigen presentation (tap) in colorectal cancer. Am J Pathol. 1994;145(3):505–509.
  • Seliger B, Höhne A, Knuth A, Bernhard H, Ehring B, Tampé R, Huber C. Reduced membrane major histocompatibility complex class i density and stability in a subset of human renal cell carcinomas with low tap and lmp expression. Clin Cancer Res. 1996;2(8):1427–1433.
  • Vitale M, Rezzani R, Rodella L, Zauli G, Grigolato P, Cadei M, Hicklin DJ, Ferrone S. Hla class i antigen and transporter associated with antigen processing (tap1 and tap2) down-regulation in high-grade primary breast carcinoma lesions. Cancer Res. 1998;58(4):737–742.
  • Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP, Bjorgaard SL, Hammond MR, Vitzthum H, Blackmon SM, et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun. 2017;8(1):1136. doi:10.1038/s41467-017-01062-w.
  • Nie Y, Yang G, Song Y, Zhao X, So C, Liao J, Wang LD, Yang CS. DNA hypermethylation is a mechanism for loss of expression of the hla class i genes in human esophageal squamous cell carcinomas. Carcinogenesis. 2001;22(10):1615–1623. doi:10.1093/carcin/22.10.1615.
  • Taylor BC, Balko JM. Mechanisms of mhc-i downregulation and role in immunotherapy response. Front Immunol. 2022;13(844866). doi:10.3389/fimmu.2022.844866.
  • Lazaridou MF, Gonschorek E, Massa C, Friedrich M, Handke D, Mueller A, Jasinski-Bergner S, Dummer R, Koelblinger P, Seliger B. Identification of mir-200a-5p targeting the peptide transporter tap1 and its association with the clinical outcome of melanoma patients. Oncoimmunology. 2020;9(1):1774323. doi:10.1080/2162402X.2020.1774323.
  • Colangelo T, Polcaro G, Ziccardi P, Pucci B, Muccillo L, Galgani M, Fucci A, Milone MR, Budillon A, Santopaolo M, et al. Proteomic screening identifies calreticulin as a mir-27a direct target repressing mhc class i cell surface exposure in colorectal cancer. Cell Death Disease. 2016;7(2):e2120. doi:10.1038/cddis.2016.28.
  • Yi M, Xu L, Jiao Y, Luo S, Li A, Wu K. The role of cancer-derived micrornas in cancer immune escape. J Hematol Oncol. 2020;13(1):25. doi:10.1186/s13045-020-00848-8.
  • Park HS, Cho U, Im SY, Yoo CY, Jung JH, Suh YJ, Choi HJ. Loss of human leukocyte antigen class i expression is associated with poor prognosis in patients with advanced breast cancer. J Pathol Transl Med. 2019;53(2):75–85. doi:10.4132/jptm.2018.10.11.
  • Hanagiri T, Shigematsu Y, Kuroda K, Baba T, Shiota H, Ichiki Y, Nagata Y, Yasuda M, Uramoto H, So T, et al. Prognostic implications of human leukocyte antigen class i expression in patients who underwent surgical resection for non-small-cell lung cancer. J Surg Res. 2013;181(2):e57–63. doi:10.1016/j.jss.2012.07.029.
  • Liu WM, Fowler DW, Smith P, Dalgleish AG. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer. 2010;102(1):115–123. doi:10.1038/sj.bjc.6605465.
  • Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015;28(6):690–714. doi:10.1016/j.ccell.2015.10.012.
  • Messaoudene M, Mourikis TP, Michels J, Fu Y, Bonvalet M, Lacroix-Trikki M, Routy B, Fluckiger A, Rusakiewicz S, Roberti MP, et al. T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for mhc class i loss variants. Ann Oncol. 2019;30(6):934–944. doi:10.1093/annonc/mdz112.
  • Garnett CT, Palena C, Chakraborty M, Tsang KY, Schlom J, Hodge JW. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic t lymphocytes. Cancer Res. 2004;64(21):7985–7994. doi:10.1158/0008-5472.CAN-04-1525.
  • Zhou F. Molecular mechanisms of ifn-gamma to up-regulate mhc class i antigen processing and presentation. Int Rev Immunol. 2009;28(3–4):239–260. doi:10.1080/08830180902978120.
  • Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-γ. Annu Rev Immunol. 1997;15(1):15(749–795. doi:10.1146/annurev.immunol.15.1.749.
  • Propper DJ, Chao D, Braybrooke JP, Bahl P, Thavasu P, Balkwill F, Turley H, Dobbs N, Gatter K, Talbot DC, et al. Low-dose ifn-gamma induces tumor mhc expression in metastatic malignant melanoma. Clin Cancer Res. 2003;9(1):84–92.
  • Gu SS, Zhang W, Wang X, Jiang P, Traugh N, Li Z, Meyer C, Stewig B, Xie Y, Bu X, et al. Therapeutically increasing mhc-i expression potentiates immune checkpoint blockade. Cancer Discov. 2021;11(6):1524–1541. doi:10.1158/2159-8290.CD-20-0812.
  • Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, et al. Cdk4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471–475. doi:10.1038/nature23465.
  • Kobayashi KS, van den Elsen PJ. Nlrc5: a key regulator of mhc class i-dependent immune responses. Nat Rev Immunol. 2012;12(12):813–820. doi:10.1038/nri3339.
  • Krenciute G, Prinzing BL, Yi Z, Wu MF, Liu H, Dotti G, Balyasnikova IV, Gottschalk S. Transgenic expression of il15 improves antiglioma activity of il13rα2-car t cells but results in antigen loss variants. Cancer Immunol Res. 2017;5(7):571–581. doi:10.1158/2326-6066.CIR-16-0376.
  • Ruella M, Maus MV. Catch me if you can: leukemia escape after cd19-directed t cell immunotherapies. Comput Struct Biotechnol J. 2016. 14:14(357–362. doi:10.1016/j.csbj.2016.09.003.
  • Marofi F, Motavalli R, Safonov VA, Thangavelu L, Yumashev AV, Alexander M, Shomali N, Chartrand MS, Pathak Y, Jarahian M, et al. Car t cells in solid tumors: challenges and opportunities. Stem Cell Res Ther. 2021;12(1):81. doi:10.1186/s13287-020-02128-1.
  • Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer. 2016;16(3):131–144. doi:10.1038/nrc.2016.14.
  • Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180–190. doi:10.1038/nri3156.
  • Conlon KC, Miljkovic MD, Waldmann TA. Cytokines in the treatment of cancer. J Interferon Cytokine Res. 2019;39(1):6–21. doi:10.1089/jir.2018.0019.
  • Liu Y, Zhou N, Zhou L, Wang J, Zhou Y, Zhang T, Fang Y, Deng J, Gao Y, Liang X, et al. Il-2 regulates tumor-reactive cd8(+) t cell exhaustion by activating the aryl hydrocarbon receptor. Nat Immunol. 2021;22(3):358–369. doi:10.1038/s41590-020-00850-9.
  • Mlecnik B, Bindea G, Angell HK, Sasso MS, Obenauf AC, Fredriksen T, Lafontaine L, Bilocq AM, Kirilovsky A, Tosolini M, et al. Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. Sci Transl Med. 2014;6(228):ra228237–ra228237. doi:10.1126/scitranslmed.3007240.
  • Baldo BA. Side effects of cytokines approved for therapy. Drug Saf. 2014;37(11):921–943. doi:10.1007/s40264-014-0226-z.
  • Deckers J, Anbergen T, Hokke AM, de Dreu A, Schrijver DP, de Bruin K, Toner YC, Beldman TJ, Spangler JB, de Greef TFA, et al. Engineering cytokine therapeutics. Nat Rev Bioengin. 2023;1(4):286–303. doi:10.1038/s44222-023-00030-y.
  • Guo J, Liang Y, Xue D, Shen J, Cai Y, Zhu J, Fu YX, Peng H. Tumor-conditional il-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity. Cell Res. 2021;31(11):1190–1198. doi:10.1038/s41422-021-00543-4.
  • Hsu EJ, Cao X, Moon B, Bae J, Sun Z, Liu Z, Fu Y-X. A cytokine receptor-masked il2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy. Nat Commun. 2021;12(1):2768. doi:10.1038/s41467-021-22980-w.
  • Mortezaee K, Majidpoor J. Checkpoint inhibitor/interleukin-based combination therapy of cancer. Cancer Med. 2022;11(15):2934–2943. doi:10.1002/cam4.4659.
  • Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara HMCS, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Seminars In Cancer Biology. 2015;35:35(S185–S198. doi:10.1016/j.semcancer.2015.03.004.
  • Briukhovetska D, Dörr J, Endres S, Libby P, Dinarello CA, Kobold S. Interleukins in cancer: from biology to therapy. Nat Rev Cancer. 2021;21(8):481–499. doi:10.1038/s41568-021-00363-z.
  • Shinriki S, Jono H, Ota K, Ueda M, Kudo M, Ota T, Oike Y, Endo M, Ibusuki M, Hiraki A, et al. Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res. 2009;15(17):5426–5434. doi:10.1158/1078-0432.CCR-09-0287.
  • Tsukamoto H, Fujieda K, Miyashita A, Fukushima S, Ikeda T, Kubo Y, Senju S, Ihn H, Nishimura Y, Oshiumi H. Combined blockade of il6 and pd-1/pd-l1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res. 2018;78(17):5011–5022. doi:10.1158/0008-5472.CAN-18-0118.
  • Liu H, Shen J, Lu K. Il-6 and pd-l1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model. Biochem Bioph Res Co. 2017;486(2):239–244. doi:10.1016/j.bbrc.2017.02.128.
  • Weber R, Groth C, Lasser S, Arkhypov I, Petrova V, Altevogt P, Utikal J, Umansky V. Il-6 as a major regulator of mdsc activity and possible target for cancer immunotherapy. Cell Immunol. 2021;359(104254):104254. doi:10.1016/j.cellimm.2020.104254.
  • Narayan V, Barber-Rotenberg JS, Jung I-Y, Lacey SF, Rech AJ, Davis MM, Hwang W-T, Lal P, Carpenter EL, Maude SL, et al. Psma-targeting tgfβ-insensitive armored car t cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2022;28(4):724–734. doi:10.1038/s41591-022-01726-1.
  • Junghans RP, Ma Q, Rathore R, Gomes EM, Bais AJ, Lo AS, Abedi M, Davies RA, Cabral HJ, Al-Homsi AS, et al. Phase i trial of anti-psma designer car-t cells in prostate cancer: possible role for interacting interleukin 2-t cell pharmacodynamics as a determinant of clinical response. The Prostate. 2016;76(14):1257–1270. doi:10.1002/pros.23214.
  • Massagué J, Wotton D. Transcriptional control by the tgf-beta/smad signaling system. EMBO J. 2000;19(8):1745–1754. doi:10.1093/emboj/19.8.1745.
  • Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE III, Koeppen H, Astarita JL, Cubas R, et al. Tgfβ attenuates tumour response to pd-l1 blockade by contributing to exclusion of t cells. Nature. 2018;554(7693):544–548. doi:10.1038/nature25501.
  • Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, Sevillano M, Ibiza S, Cañellas A, Hernando-Momblona X, et al. Tgfβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554(7693):538–543. doi:10.1038/nature25492.
  • Greco R, Qu H, Qu H, Theilhaber J, Shapiro G, Gregory R, Winter C, Malkova N, Sun F, Jaworski J, et al. Pan-tgfβ inhibition by sar439459 relieves immunosuppression and improves antitumor efficacy of pd-1 blockade. Oncoimmunology. 2020;9(1):1811605. doi:10.1080/2162402X.2020.1811605.
  • Martin CJ, Datta A, Littlefield C, Kalra A, Chapron C, Wawersik S, Dagbay KB, Brueckner CT, Nikiforov A, Danehy FT Jr., et al. Selective inhibition of tgfβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Sci Transl Med. 2020;12(536). doi:10.1126/scitranslmed.aay8456.
  • Lan Y, Moustafa M, Knoll M, Xu C, Furkel J, Lazorchak A, Yeung TL, Hasheminasab SM, Jenkins MH, Meister S, et al. Simultaneous targeting of tgf-β/pd-l1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Cancer Cell. 2021;39(10):1388–1403.e1310. doi:10.1016/j.ccell.2021.08.008.
  • Anderton MJ, Mellor HR, Bell A, Sadler C, Pass M, Powell S, Steele SJ, Roberts RR, Heier A. Induction of heart valve lesions by small-molecule alk5 inhibitors. Toxicol Pathol. 2011;39(6):916–924. doi:10.1177/0192623311416259.
  • Mitra MS, Lancaster K, Adedeji AO, Palanisamy GS, Dave RA, Zhong F, Holdren MS, Turley SJ, Liang W-C, Wu Y, et al. A potent pan-tgfβ neutralizing monoclonal antibody elicits cardiovascular toxicity in mice and cynomolgus monkeys. Toxicol Sci. 2020;175(1):24–34. doi:10.1093/toxsci/kfaa024.
  • Gueorguieva I, Cleverly AL, Stauber A, Sada Pillay N, Rodon JA, Miles CP, Yingling JM, Lahn MM. Defining a therapeutic window for the novel tgf-β inhibitor ly2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model. Br J Clin Pharmacol. 2014;77(5):796–807. doi:10.1111/bcp.12256.
  • Brandes AA, Carpentier AF, Kesari S, Sepulveda-Sanchez JM, Wheeler HR, Chinot O, Cher L, Steinbach JP, Capper D, Specenier P, et al. A phase ii randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro Oncol. 2016;18(8):1146–1156. doi:10.1093/neuonc/now009.
  • Haque S, Morris JC. Transforming growth factor-β: a therapeutic target for cancer. Hum Vaccin Immunother. 2017;13(8):1741–1750. doi:10.1080/21645515.2017.1327107.
  • Melisi D, Garcia-Carbonero R, Macarulla T, Pezet D, Deplanque G, Fuchs M, Trojan J, Oettle H, Kozloff M, Cleverly A, et al. Galunisertib plus gemcitabine vs. Gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br J Cancer. 2018;119(10):1208–1214. doi:10.1038/s41416-018-0246-z.
  • Robbrecht D, Doger B, Grob J-J, Bechter OE, de Miguel MJ, Vieito M, Schadendorf D, Curigliano G, Borbath I, Butler MO, et al. Safety and efficacy results from the expansion phase of the first-in-human study evaluating tgfβ inhibitor sar439459 alone and combined with cemiplimab in adults with advanced solid tumors. J Clin Oncol. 2022;40(16_suppl):2524–2524. doi:10.1200/JCO.2022.40.16_suppl.2524.
  • Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, Kempers MJ, Fishman EK, Chen Y, Myers L, et al. Loss-of-function mutations in tgfb2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012;44(8):922–927. doi:10.1038/ng.2349.
  • Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JMA, de Graaf BM, van de Beek G, Gallo E, Kruithof BPT, Venselaar H, Myers LA, et al. Mutations in a tgf-β ligand, tgfb3, cause syndromic aortic aneurysms and dissections. J Am Coll Cardiol. 2015;65(13):1324–1336. doi:10.1016/j.jacc.2015.01.040.
  • Ozga AJ, Chow MT, Luster AD. Chemokines and the immune response to cancer. Immunity. 2021;54(5):859–874. doi:10.1016/j.immuni.2021.01.012.
  • Tu MM, Abdel-Hafiz HA, Jones RT, Jean A, Hoff KJ, Duex JE, Chauca-Diaz A, Costello JC, Dancik GM, Tamburini BAJ, et al. Inhibition of the ccl2 receptor, ccr2, enhances tumor response to immune checkpoint therapy. Commun Biol. 2020;3(1):720. doi:10.1038/s42003-020-01441-y.
  • Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, Xu C, McKenzie JA, Zhang C, Liang X, et al. Loss of pten promotes resistance to t cell–mediated immunotherapy. Cancer Discov. 2016;6(2):202–216. doi:10.1158/2159-8290.CD-15-0283.
  • Haag GM, Springfeld C, Grün B, Apostolidis L, Zschäbitz S, Dietrich M, Berger A-K, Weber TF, Zoernig I, Schaaf M, et al. Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer – the piccasso phase i trial. Eur J Cancer. 2022;167:167(112–122. doi:10.1016/j.ejca.2022.03.017.
  • Liu G, Rui W, Zhao X, Lin X. Enhancing car-t cell efficacy in solid tumors by targeting the tumor microenvironment. Cell Mol Immunol. 2021;18(5):1085–1095. doi:10.1038/s41423-021-00655-2.
  • He X, Xu C. Immune checkpoint signaling and cancer immunotherapy. Cell Res. 2020;30(8):660–669. doi:10.1038/s41422-020-0343-4.
  • Ngiow SF, Young A, Jacquelot N, Yamazaki T, Enot D, Zitvogel L, Smyth MJ. A threshold level of intratumor cd8+ t-cell pd1 expression dictates therapeutic response to anti-pd1. Cancer Res. 2015;75(18):3800–3811. doi:10.1158/0008-5472.CAN-15-1082.
  • Lefler DS, Snook AE, Bashir B. Immune checkpoint inhibitors in luminal gastrointestinal malignancies: going beyond msi-h/dmmr, tmb and pd-l1. Immunotherapy. 2022;14(11):885–902. doi:10.2217/imt-2022-0012.
  • Gandini S, Massi D, Mandalà M. Pd-l1 expression in cancer patients receiving anti pd-1/pd-l1 antibodies: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2016. 100:100(88–98. doi:10.1016/j.critrevonc.2016.02.001.
  • Doroshow DB, Bhalla S, Beasley MB, Sholl LM, Kerr KM, Gnjatic S, Wistuba II, Rimm DL, Tsao MS, Hirsch FR. Pd-l1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2021;18(6):345–362. doi:10.1038/s41571-021-00473-5.
  • Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon R-A, Reed K, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–133. doi:10.1056/NEJMoa1302369.
  • Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim S-W, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020–2031. doi:10.1056/NEJMoa1910231.
  • Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–1290. doi:10.1056/NEJMoa1712126.
  • Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24–34. doi:10.1056/NEJMoa2109970.
  • Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H, et al. Adaptive resistance to therapeutic pd-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7(10501). doi:10.1038/ncomms10501.
  • Sasikumar PG, Sudarshan NS, Adurthi S, Ramachandra RK, Samiulla DS, Lakshminarasimhan A, Ramanathan A, Chandrasekhar T, Dhudashiya AA, Talapati SR, et al. Pd-1 derived ca-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy. Commun Biol. 2021;4(1):699. doi:10.1038/s42003-021-02191-1.
  • Curigliano G, Gelderblom H, Mach N, Doi T, Tai D, Forde PM, Sarantopoulos J, Bedard PL, Lin CC, Hodi FS, et al. Phase i/ib clinical trial of sabatolimab, an anti-tim-3 antibody, alone and in combination with spartalizumab, an anti-pd-1 antibody, in advanced solid tumors. Clin Cancer Res. 2021;27(13):3620–3629. doi:10.1158/1078-0432.CCR-20-4746.
  • Choi J, Medikonda R, Saleh L, Kim T, Pant A, Srivastava S, Kim YH, Jackson C, Tong L, Routkevitch D, et al. Combination checkpoint therapy with anti-pd-1 and anti-btla results in a synergistic therapeutic effect against murine glioblastoma. Oncoimmunology. 2021;10(1):1956142. doi:10.1080/2162402X.2021.1956142.
  • Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, Bettini ML, Gravano DM, Vogel P, Liu CL, et al. Immune inhibitory molecules lag-3 and pd-1 synergistically regulate t-cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917–927. doi:10.1158/0008-5472.CAN-11-1620.
  • Sung E, Ko M, Won JY, Jo Y, Park E, Kim H, Choi E, Jung UJ, Jeon J, Kim Y, et al. Lag-3xpd-l1 bispecific antibody potentiates antitumor responses of t cells through dendritic cell activation. Mol Ther. 2022;30(8):2800–2816. doi:10.1016/j.ymthe.2022.05.003.
  • Liu J, Luan Y, Deng H, Wang F, Wang C, Zhang Z. A bivalent tim-3/pd-1 bispecific antibody for the treatment of pd-1 antibody resistant or refractory nsclc. J Clin Oncol. 2022;40(16_suppl):e14597–e14597. doi:10.1200/JCO.2022.40.16_suppl.e14597.
  • Chen N, Morello A, Tano Z, Adusumilli PS. Car t-cell intrinsic pd-1 checkpoint blockade: a two-in-one approach for solid tumor immunotherapy. Oncoimmunology. 2017;6(2):e1273302. doi:10.1080/2162402X.2016.1273302.
  • Tian Y, Li Y, Shao Y, Zhang Y. Gene modification strategies for next-generation car t cells against solid cancers. J Hematol Oncol. 2020;13(1):54. doi:10.1186/s13045-020-00890-6.
  • Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF, Maus MV, Fraietta JA, Zhao Y, June CH. Dominant-negative tgf-β receptor enhances psma-targeted human car t cell proliferation and augments prostate cancer eradication. Mol Ther. 2018;26(7):1855–1866. doi:10.1016/j.ymthe.2018.05.003.
  • Kamphorst AO, Wieland A, Nasti T, Yang S, Zhang R, Barber DL, Konieczny BT, Daugherty CZ, Koenig L, Yu K, et al. Rescue of exhausted cd8 t cells by pd-1-targeted therapies is cd28-dependent. Science. 2017;355(6332):1423–1427. doi:10.1126/science.aaf0683.
  • Cappell KM, Kochenderfer JN. A comparison of chimeric antigen receptors containing cd28 versus 4-1bb costimulatory domains. Nat Rev Clin Oncol. 2021;18(11):715–727. doi:10.1038/s41571-021-00530-z.
  • Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. Cytokine storm in a phase 1 trial of the anti-cd28 monoclonal antibody tgn1412. N Engl J Med. 2006;355(10):1018–1028. doi:10.1056/NEJMoa063842.
  • Qiao Y, Qiu Y, Ding J, Luo N, Wang H, Ling X, Sun J, Wu Z, Wang Y, Liu Y, et al. Cancer immune therapy with pd-1-dependent cd137 co-stimulation provides localized tumour killing without systemic toxicity. Nat Commun. 2021;12(1):6360. doi:10.1038/s41467-021-26645-6.
  • Buchan SL, Fallatah M, Thirdborough SM, Taraban VY, Rogel A, Thomas LJ, Penfold CA, He LZ, Curran MA, Keler T, et al. Pd-1 blockade and cd27 stimulation activate distinct transcriptional programs that synergize for cd8(+) t-cell-driven antitumor immunity. Clin Cancer Res. 2018;24(10):2383–2394. doi:10.1158/1078-0432.CCR-17-3057.
  • Bronte V, Brandau S, Chen S-H, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7(1):12150. doi:10.1038/ncomms12150.
  • Hao Z, Li R, Wang Y, Li S, Hong Z, Han Z. Landscape of myeloid-derived suppressor cell in tumor immunotherapy. Biomarker Res. 2021;9(1):77. doi:10.1186/s40364-021-00333-5.
  • Wu L, Zhang XH. Tumor-associated neutrophils and macrophages-heterogenous but not chaotic. Front Immunol. 2020;11(553967). doi:10.3389/fimmu.2020.553967.
  • Wu K, Tan MY, Jiang JT, Mu XY, Wang JR, Zhou WJ, Wang X, Li MQ, He YY, Liu ZH. Cisplatin inhibits the progression of bladder cancer by selectively depleting g-mdscs: a novel chemoimmunomodulating strategy. Clin Immunol. 2018. 193:193(60–69. doi:10.1016/j.clim.2018.01.012.
  • Li T, Liu T, Zhu W, Xie S, Zhao Z, Feng B, Guo H, Yang R. Targeting mdsc for immune-checkpoint blockade in cancer immunotherapy: Current progress and new prospects. Clin Med Insights Oncol. 2021. 15:11795549211035540. doi:10.1177/11795549211035540.
  • Kim NR, Kim YJ. Oxaliplatin regulates myeloid-derived suppressor cell-mediated immunosuppression via downregulation of nuclear factor-κb signaling. Cancer Med. 2019;8(1):276–288. doi:10.1002/cam4.1878.
  • Koinis F, Vetsika EK, Aggouraki D, Skalidaki E, Koutoulaki A, Gkioulmpasani M, Georgoulias V, Kotsakis A. Effect of first-line treatment on myeloid-derived suppressor cells’ subpopulations in the peripheral blood of patients with non-small cell lung cancer. J Thorac Oncol. 2016;11(8):1263–1272. doi:10.1016/j.jtho.2016.04.026.
  • Li K, Shi H, Zhang B, Ou X, Ma Q, Chen Y, Shu P, Li D, Wang Y. Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer. Signal Transduct Target Ther. 2021;6(1):362. doi:10.1038/s41392-021-00670-9.
  • Hellmann MD, Jänne PA, Opyrchal M, Hafez N, Raez LE, Gabrilovich DI, Wang F, Trepel JB, Lee M-J, Yuno A, et al. Entinostat plus pembrolizumab in patients with metastatic nsclc previously treated with anti–pd-(l)1 therapy. Clin Cancer Res. 2021;27(4):1019–1028. doi:10.1158/1078-0432.CCR-20-3305.
  • Raggi F, Pelassa S, Pierobon D, Penco F, Gattorno M, Novelli F, Eva A, Varesio L, Giovarelli M, Bosco MC. Regulation of human macrophage m1-m2 polarization balance by hypoxia and the triggering receptor expressed on myeloid cells-1. Front Immunol. 2017;8(1097). doi:10.3389/fimmu.2017.01097.
  • Wu Q, Zhou W, Yin S, Zhou Y, Chen T, Qian J, Su R, Hong L, Lu H, Zhang F, et al. Blocking triggering receptor expressed on myeloid cells-1-positive tumor-associated macrophages induced by hypoxia reverses immunosuppression and anti-programmed cell death ligand 1 resistance in liver cancer. Hepatology. 2019;70(1):198–214. doi:10.1002/hep.30593.
  • Laoui D, Van Overmeire E, De Baetselier P, Van Ginderachter JA, Raes G. Functional relationship between tumor-associated macrophages and macrophage colony-stimulating factor as contributors to cancer progression. Front Immunol. 2014;5(489). doi:10.3389/fimmu.2014.00489.
  • Voissière A, Gomez-Roca C, Chabaud S, Rodriguez C, Nkodia A, Berthet J, Montane L, Bidaux A-S, Treilleux I, Eberst L, et al. The csf-1r inhibitor pexidartinib impacts dendritic cell differentiation through inhibition of flt3 signaling and may antagonize the effect of durvalumab in patients with advanced cancer – results from a phase 1 study. medRxiv. 2023; 2023.2002.2015.23285939. doi: 10.1101/2023.02.15.23285939
  • Zheng Y, Wang PP, Fu Y, Chen Y-y, Ding Z-Y. Zoledronic acid enhances the efficacy of immunotherapy in non-small cell lung cancer. Int Immunopharmacol. 2022;110(109030). doi:10.1016/j.intimp.2022.109030.
  • Togashi Y, Shitara K, Nishikawa H. Regulatory t cells in cancer immunosuppression — implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16(6):356–371. doi:10.1038/s41571-019-0175-7.
  • Jacobs JF, Punt CJ, Lesterhuis WJ, Sutmuller RP, Brouwer HM, Scharenborg NM, Klasen IS, Hilbrands LB, Figdor CG, de Vries IJ, et al. Dendritic cell vaccination in combination with anti-cd25 monoclonal antibody treatment: a phase i/ii study in metastatic melanoma patients. Clin Cancer Res. 2010;16(20):5067–5078. doi:10.1158/1078-0432.CCR-10-1757.
  • Doi T, Muro K, Ishii H, Kato T, Tsushima T, Takenoyama M, Oizumi S, Gemmoto K, Suna H, Enokitani K, et al. A phase i study of the anti-cc chemokine receptor 4 antibody, mogamulizumab, in combination with nivolumab in patients with advanced or metastatic solid tumors. Clin Cancer Res. 2019;25(22):6614–6622. doi:10.1158/1078-0432.CCR-19-1090.
  • Zamarin D, Hamid O, Nayak-Kapoor A, Sahebjam S, Sznol M, Collaku A, Fox FE, Marshall MA, Hong DS. Mogamulizumab in combination with durvalumab or tremelimumab in patients with advanced solid tumors: A phase i study. Clin Cancer Res. 2020;26(17):4531–4541. doi:10.1158/1078-0432.CCR-20-0328.
  • Madondo MT, Quinn M, Plebanski M. Low dose cyclophosphamide: mechanisms of t cell modulation. Cancer Treat Rev. 2016. 42:42(3–9. doi:10.1016/j.ctrv.2015.11.005.
  • Ping Q, Yan R, Cheng X, Wang W, Zhong Y, Hou Z, Shi Y, Wang C, Li R. Cancer-associated fibroblasts: overview, progress, challenges, and directions. Cancer Gene Ther. 2021;28(9):984–999. doi:10.1038/s41417-021-00318-4.
  • Glabman RA, Choyke PL, Sato N. Cancer-associated fibroblasts: tumorigenicity and targeting for cancer therapy. Cancers Basel. 2022;14(16):3906. doi:10.3390/cancers14163906.
  • Ham IH, Lee D, Hur H. Cancer-associated fibroblast-induced resistance to chemotherapy and radiotherapy in gastrointestinal cancers. Cancers Basel. 2021;13(5):1172. doi:10.3390/cancers13051172.
  • Yoon H, Tang C-M, Banerjee S, Delgado AL, Yebra M, Davis J, Sicklick JK. Tgf-β1-mediated transition of resident fibroblasts to cancer-associated fibroblasts promotes cancer metastasis in gastrointestinal stromal tumor. Oncogenesis. 2021;10(2):13. doi:10.1038/s41389-021-00302-5.
  • Morén A, Bellomo C, Tsubakihara Y, Kardassis D, Mikulits W, Heldin CH, Moustakas A. Lxrα limits tgfβ-dependent hepatocellular carcinoma associated fibroblast differentiation. Oncogenesis. 2019;8(6):36. doi:10.1038/s41389-019-0140-4.
  • Freedman JD, Duffy MR, Lei-Rossmann J, Muntzer A, Scott EM, Hagel J, Campo L, Bryant RJ, Verrill C, Lambert A, et al. An oncolytic virus expressing a t-cell engager simultaneously targets cancer and immunosuppressive stromal cells. Cancer Res. 2018;78(24):6852–6865. doi:10.1158/0008-5472.CAN-18-1750.
  • Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, et al. Targeting cxcl12 from fap-expressing carcinoma-associated fibroblasts synergizes with anti-pd-l1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212–20217. doi:10.1073/pnas.1320318110.
  • Ford K, Hanley CJ, Mellone M, Szyndralewiez C, Heitz F, Wiesel P, Wood O, Machado M, Lopez MA, Ganesan AP, et al. Nox4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated cd8 t-cell exclusion from tumors. Cancer Res. 2020;80(9):1846–1860. doi:10.1158/0008-5472.CAN-19-3158.
  • Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T, Bordbar D, Shan D, Samanamud J, Mahajan A, et al. Immune and genomic correlates of response to anti-pd-1 immunotherapy in glioblastoma. Nat Med. 2019;25(3):462–469. doi:10.1038/s41591-019-0349-y.
  • Yeh C-H, Bellon M, Nicot C. Fbxw7: a critical tumor suppressor of human cancers. Mol Cancer. 2018;17(1):115. doi:10.1186/s12943-018-0857-2.
  • Gstalder C, Liu D, Miao D, Lutterbach B, DeVine AL, Lin C, Shettigar M, Pancholi P, Buchbinder EI, Carter SL, et al. Inactivation of fbxw7 impairs dsrna sensing and confers resistance to pd-1 blockade. Cancer Discov. 2020;10(9):1296–1311. doi:10.1158/2159-8290.CD-19-1416.
  • Koyama S, Akbay EA, Li YY, Aref AR, Skoulidis F, Herter-Sprie GS, Buczkowski KA, Liu Y, Awad MM, Denning WL, et al. Stk11/lkb1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress t-cell activity in the lung tumor microenvironment. Cancer Res. 2016;76(5):999–1008. doi:10.1158/0008-5472.CAN-15-1439.
  • Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, Schrock AB, Hartmaier RJ, Trabucco SE, Gay L, et al. Stk11/lkb1 mutations and pd-1 inhibitor resistance in kras-mutant lung adenocarcinoma. Cancer Discov. 2018;8(7):822–835. doi:10.1158/2159-8290.CD-18-0099.
  • Wang J, Sun J, Zhang N, Yang R, Li H, Zhang Y, Chen K, Kong D. Pes1 enhances proliferation and tumorigenesis in hepatocellular carcinoma via the pi3k/akt pathway. Life Sci. 2019. 219:219(182–189. doi:10.1016/j.lfs.2018.12.054.
  • Ma N, Hua R, Yang Y, Liu Z-C, Pan J, Yu B-Y, Sun Y-F, Xie D, Wang Y, Li Z-G. Pes1 reduces cd8+ t cell infiltration and immunotherapy sensitivity via interrupting ilf3-il15 complex in esophageal squamous cell carcinoma. J Biomed Sci. 2023;30(1):20. doi:10.1186/s12929-023-00912-8.
  • Ala M. Target c-myc to treat pancreatic cancer. Cancer Biol Ther. 2022;23(1):34–50. doi:10.1080/15384047.2021.2017223.
  • Jin X, Fang R, Fan P, Zeng L, Zhang B, Lu X, Liu T. Pes1 promotes bet inhibitors resistance and cells proliferation through increasing c-myc expression in pancreatic cancer. J Exp Clin Cancer Res. 2019;38(1):463. doi:10.1186/s13046-019-1466-7.
  • Ham SW, Jeon H-Y, Jin X, Kim E-J, Kim J-K, Shin YJ, Lee Y, Kim SH, Lee SY, Seo S, et al. Tp53 gain-of-function mutation promotes inflammation in glioblastoma. Cell Death Differ. 2019;26(3):409–425. doi:10.1038/s41418-018-0126-3.
  • Dong Z-Y, Zhong W-Z, Zhang X-C, Su J, Xie Z, Liu S-Y, Tu H-Y, Chen H-J, Sun Y-L, Zhou Q, et al. Potential predictive value of tp53 and kras mutation status for response to pd-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res. 2017;23(12):3012–3024. doi:10.1158/1078-0432.CCR-16-2554.
  • Chen X, Zhang T, Su W, Dou Z, Zhao D, Jin X, Lei H, Wang J, Xie X, Cheng B, et al. Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Disease. 2022;13(11):974. doi:10.1038/s41419-022-05408-1.
  • Xiao Y, Chen J, Zhou H, Zeng X, Ruan Z, Pu Z, Jiang X, Matsui A, Zhu L, Amoozgar Z, et al. Combining p53 mrna nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy. Nat Commun. 2022;13(1):758. doi:10.1038/s41467-022-28279-8.
  • Nagahashi M, Sato S, Yuza K, Shimada Y, Ichikawa H, Watanabe S, Takada K, Okamoto T, Okuda S, Lyle S, et al. Common driver mutations and smoking history affect tumor mutation burden in lung adenocarcinoma. J Surg Res. 2018;230:230(181–185. doi:10.1016/j.jss.2018.07.007.
  • Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, Huynh TG, Zhao L, Fulton L, Schultz KR, et al. Egfr mutations and alk rearrangements are associated with low response rates to pd-1 pathway blockade in non–small cell lung cancer: a retrospective analysis. Clin Cancer Res. 2016;22(18):4585–4593. doi:10.1158/1078-0432.CCR-15-3101.
  • Addeo A, Passaro A, Malapelle U, Banna GL, Subbiah V, Friedlaender A. Immunotherapy in non-small cell lung cancer harbouring driver mutations. Cancer Treat Rev. 2021. 96:96(. doi:10.1016/j.ctrv.2021.102179.
  • Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373(17):1627–1639. doi:10.1056/NEJMoa1507643.
  • Herbst RS, Baas P, Kim D-W, Felip E, Pérez-Gracia JL, Han J-Y, Molina J, Kim J-H, Arvis CD, Ahn M-J, et al. Pembrolizumab versus docetaxel for previously treated, pd-l1-positive, advanced non-small-cell lung cancer (keynote-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–1550. doi:10.1016/S0140-6736(15)01281-7.
  • Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (oak): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–265. doi:10.1016/S0140-6736(16)32517-X.
  • Peters S, Gettinger S, Johnson ML, Jänne PA, Garassino MC, Christoph D, Toh CK, Rizvi NA, Chaft JE, Carcereny Costa E, et al. Phase ii trial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1–selected advanced non–small-cell lung cancer (birch). J Clin Oncol. 2017;35(24):2781–2789. doi:10.1200/JCO.2016.71.9476.
  • Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous nsclc. N Engl J Med. 2018;378(24):2288–2301. doi:10.1056/NEJMoa1716948.
  • Garassino MC, Cho B-C, Kim J-H, Mazières J, Vansteenkiste J, Lena H, Corral Jaime J, Gray JE, Powderly J, Chouaid C, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (atlantic): an open-label, single-arm, phase 2 study. Lancet Oncol. 2018;19(4):521–536. doi:10.1016/S1470-2045(18)30144-X.
  • Passaro A, Jänne PA, Mok T, Peters S. Overcoming therapy resistance in egfr-mutant lung cancer. Nat Cancer. 2021;2(4):377–391. doi:10.1038/s43018-021-00195-8.
  • Oxnard GR, Yang JCH, Yu H, Kim SW, Saka H, Horn L, Goto K, Ohe Y, Mann H, Thress KS, et al. Tatton: A multi-arm, phase ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in egfr-mutant lung cancer. Ann Oncol. 2020;31(4):507–516. doi:10.1016/j.annonc.2020.01.013.
  • Yang J-H, Shepherd FA, Kim D-W, Lee G-W, Lee JS, Chang G-C, Lee SS, Wei Y-F, Lee YG, Laus G, et al. Osimertinib plus durvalumab versus osimertinib monotherapy in egfr t790m–positive nsclc following previous egfr tki therapy: caural brief report. J Thorac Oncol. 2019;14(5):933–939. doi:10.1016/j.jtho.2019.02.001.
  • Yang J-H, Lee DH, Lee J-S, Fan Y, de Marinis F, Okamoto I, Inoue T, Rodriguez Cid JR, Zhang L, Yang C-T, et al. Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (tki)-resistant, egfr-mutant, metastatic nonsquamous nsclc: phase 3 keynote-789 study. J Clin Oncol. 2023;41(17_suppl):LBA9000–LBA9000. doi:10.1200/JCO.2023.41.17_suppl.LBA9000.
  • Mok TSK, Nakagawa K, Park K, Ohe Y, Girard N, Kim HR, Wu YL, Gainor J, Lee SH, Chiu CH, et al. Lba8 nivolumab (nivo) + chemotherapy (chemo) vs chemo in patients (pts) with egfr-mutated metastatic non-small cell lung cancer (mnsclc) with disease progression after egfr tyrosine kinase inhibitors (tkis) in checkmate 722. Ann Oncol. 2022;33:33(S1561–S1562. doi:10.1016/j.annonc.2022.10.350.
  • Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8(6):519–530. doi:10.1085/jgp.8.6.519.
  • Singer K, Kastenberger M, Gottfried E, Hammerschmied CG, Büttner M, Aigner M, Seliger B, Walter B, Schlösser H, Hartmann A, et al. Warburg phenotype in renal cell carcinoma: high expression of glucose-transporter 1 (glut-1) correlates with low cd8+ t-cell infiltration in the tumor. Int J Cancer. 2011;128(9):2085–2095. doi:10.1002/ijc.25543.
  • Ho P-C, Bihuniak Jessica D, Macintyre Andrew N, Staron M, Liu X, Amezquita R, Tsui Y-C, Cui G, Micevic G, Perales Jose C, et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor t cell responses. Cell. 2015;162(6):1217–1228. doi:10.1016/j.cell.2015.08.012.
  • Marchiq I, Pouysségur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/h(+) symporters. J Mol Med (Berl). 2016;94(2):155–171. doi:10.1007/s00109-015-1307-x.
  • Ramapriyan R, Caetano MS, Barsoumian HB, Mafra ACP, Zambalde EP, Menon H, Tsouko E, Welsh JW, Cortez MA. Altered cancer metabolism in mechanisms of immunotherapy resistance. Pharmacology & Therapeutics. 2019. 195:162–171. doi:10.1016/j.pharmthera.2018.11.004.
  • Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, Damaghi M, Wojtkowiak JW, Mulé JJ, Ibrahim-Hashim A, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 2016;76(6):1381–1390. doi:10.1158/0008-5472.CAN-15-1743.
  • Hamaguchi R, Isowa M, Narui R, Morikawa H, Wada H. Clinical review of alkalization therapy in cancer treatment. Front Oncol. 2022. 12:12(. doi:10.3389/fonc.2022.1003588.
  • Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of t cell proliferation. J Immunol. 2000;164(7):3596–3599. doi:10.4049/jimmunol.164.7.3596.
  • Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9(10):1269–1274. doi:10.1038/nm934.
  • Rui Q, Chen Z, Chen-Ji W, Wei X, Jian-Yuan Z, Yan L, Yi-Yuan Y, Peng-Cheng L, Yao L, Shimin Z, et al. Tryptophan potentiates cd8+ t cells against cancer cells by trip12 tryptophanylation and surface pd-1 downregulation. J Immunother Cancer. 2021;9(7):e002840. doi:10.1136/jitc-2021-002840.
  • Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (echo-301/keynote-252): A phase 3, randomised, double-blind study. Lancet Oncol. 2019;20(8):1083–1097. doi:10.1016/S1470-2045(19)30274-8.
  • Chen S, Tan J, Zhang A. The ups, downs and new trends of ido1 inhibitors. Bioorg Chem. 2021;110(104815):104815. doi:10.1016/j.bioorg.2021.104815.
  • Liu Y, Van Ginderachter JA, Brys L, De Baetselier P, Raes G, Geldhof AB. Nitric oxide-independent ctl suppression during tumor progression: association with arginase-producing (m2) myeloid cells1. J Immunol. 2003;170(10):5064–5074. doi:10.4049/jimmunol.170.10.5064.
  • Lowe MM, Boothby I, Clancy S, Ahn RS, Liao W, Nguyen DN, Schumann K, Marson A, Mahuron KM, Kingsbury GA, et al. Regulatory t cells use arginase 2 to enhance their metabolic fitness in tissues. JCI Insight. 2019;4(24). doi:10.1172/jci.insight.129756.
  • Cheng C-T, Qi Y, Wang Y-C, Chi KK, Chung Y, Ouyang C, Chen Y-R, Oh ME, Sheng X, Tang Y, et al. Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction. Commun Biol. 2018;1(1):178. doi:10.1038/s42003-018-0178-4.
  • Pallett LJ, Dimeloe S, Sinclair LV, Byrne AJ, Schurich A. A glutamine ‘tug-of-war’: Targets to manipulate glutamine metabolism for cancer immunotherapy. Immunother Adv. 2021;1(1):ltab010. doi:10.1093/immadv/ltab010.
  • Ma G, Zhang Z, Li P, Zhang Z, Zeng M, Liang Z, Li D, Wang L, Chen Y, Liang Y, et al. Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment. Cell Commun Signal. 2022;20(1):114. doi:10.1186/s12964-022-00909-0.
  • Metzler B, Gfeller P, Guinet E. Restricting glutamine or glutamine-dependent purine and pyrimidine syntheses promotes human t cells with high foxp3 expression and regulatory properties. J Immunol. 2016;196(9):3618–3630. doi:10.4049/jimmunol.1501756.
  • Tannir NM, Agarwal N, Porta C, Lawrence NJ, Motzer R, McGregor B, Lee RJ, Jain RK, Davis N, Appleman LJ, et al. Efficacy and safety of telaglenastat plus cabozantinib vs placebo plus cabozantinib in patients with advanced renal cell carcinoma: the cantata randomized clinical trial. JAMA Oncol. 2022;8(10):1411–1418. doi:10.1001/jamaoncol.2022.3511.
  • Hanahan D, Weinberg Robert A. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi:10.1016/j.cell.2011.02.013.
  • Gadiyar V, Lahey KC, Calianese D, Devoe C, Mehta D, Bono K, Desind S, Davra V, Birge RB. Cell death in the tumor microenvironment: implications for cancer immunotherapy. Cells. 2020;9(10):2207. doi:10.3390/cells9102207.
  • Showalter A, Limaye A, Oyer JL, Igarashi R, Kittipatarin C, Copik AJ, Khaled AR. Cytokines in immunogenic cell death: applications for cancer immunotherapy. Cytokine. 2017. 97:97(123–132. doi:10.1016/j.cyto.2017.05.024.
  • Li Z, Lai X, Fu S, Ren L, Cai H, Zhang H, Gu Z, Ma X, Luo K. Immunogenic cell death activates the tumor immune microenvironment to boost the immunotherapy efficiency. Adv Sci. 2022;9(22):2201734. doi:10.1002/advs.202201734.
  • Tang S, Ning Q, Yang L, Mo Z, Tang S. Mechanisms of immune escape in the cancer immune cycle. Int Immunopharmacol. 2020;86(106700):106700. doi:10.1016/j.intimp.2020.106700.
  • Lu T, Wang S, Xu L, Zhou Q, Singla N, Gao J, Manna S, Pop L, Xie Z, Chen M, et al. Tumor neoantigenicity assessment with csin score incorporates clonality and immunogenicity to predict immunotherapy outcomes. Sci Immunol. 2020;5(44):eaaz3199. doi:10.1126/sciimmunol.aaz3199.
  • Aaes TL, Vandenabeele P. The intrinsic immunogenic properties of cancer cell lines, immunogenic cell death, and how these influence host antitumor immune responses. Cell Death Differ. 2021;28(3):843–860. doi:10.1038/s41418-020-00658-y.
  • Liu J, Fu M, Wang M, Wan D, Wei Y, Wei X. Cancer vaccines as promising immuno-therapeutics: platforms and current progress. J Hematol Oncol. 2022;15(1):28. doi:10.1186/s13045-022-01247-x.
  • Lin MJ, Svensson-Arvelund J, Lubitz GS, Marabelle A, Melero I, Brown BD, Brody JD. Cancer vaccines: the next immunotherapy frontier. Nat Cancer. 2022;3(8):911–926. doi:10.1038/s43018-022-00418-6.
  • Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin. 2017;67(1):65–85. doi:10.3322/caac.21358.
  • Formenti SC, Rudqvist N-P, Golden E, Cooper B, Wennerberg E, Lhuillier C, Vanpouille-Box C, Friedman K, Ferrari de Andrade L, Wucherpfennig KW, et al. Radiotherapy induces responses of lung cancer to ctla-4 blockade. Nat Med. 2018;24(12):1845–1851. doi:10.1038/s41591-018-0232-2.
  • Demaria S, Coleman CN, Formenti SC. Radiotherapy: changing the game in immunotherapy. Trends Cancer. 2016;2(6):286–294. doi:10.1016/j.trecan.2016.05.002.
  • Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, Garon EB, Lee P. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the keynote-001 phase 1 trial. Lancet Oncol. 2017;18(7):895–903. doi:10.1016/S1470-2045(17)30380-7.
  • Dai Z, Wang Z, Lei K, Liao J, Peng Z, Lin M, Liang P, Yu J, Peng S, Chen S, et al. Irreversible electroporation induces cd8+ t cell immune response against post-ablation hepatocellular carcinoma growth. Cancer Lett. 2021;503:503(1–10. doi:10.1016/j.canlet.2021.01.001.
  • Zhang X, Zhang Y, Chen J, Wu Y, Zhang J, Wang J. Nanosecond pulsed electric field inhibits malignant melanoma growth by inducing the change of systemic immunity. Med Oral Patol Oral Cir Bucal. 2019;24(4):e555–e561. doi:10.4317/medoral.22976.
  • Szlasa W, Janicka N, Sauer N, Michel O, Nowak B, Saczko J, Kulbacka J. Chemotherapy and physical therapeutics modulate antigens on cancer cells. Front Immunol. 2022. 13:13(. doi:10.3389/fimmu.2022.889950.
  • Silvestrini M, Pastori C, Tamakloe S, O’Brien T, Allen C, Neal R. Ep02.04-002 synergy of local treatment with pulsed electric fields and anti-pd1 checkpoint blockade. J Thorac Oncol. 2022;17(9, Supplement):S232. doi:10.1016/j.jtho.2022.07.387.
  • Pastori C, Wagh M, Nafie E, Murad F, Trikha M, Neal R. Abstract 6392: combination of pulsed electric field, immunotherapy and cisplatin significantly prolongs survival in an orthotopic breast cancer mouse model. Cancer Res. 2023;83(7_Supplement):6392–6392. doi:10.1158/1538-7445.AM2023-6392.
  • Nafie E, Wagh M, Pastori C, Trikha M, Neal R. Abstract 6638: pulsed electric fields combined with anti-pd1 prolongs survival and triggers an adaptive immune response in an io-non-responsive orthotopic mouse model. Cancer Res. 2023;83(7_Supplement):6638–6638. doi:10.1158/1538-7445.AM2023-6638.
  • Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell. 2018;33(4):570–580. doi:10.1016/j.ccell.2018.03.015.
  • Yi M, Yu S, Qin S, Liu Q, Xu H, Zhao W, Chu Q, Wu K. Gut microbiome modulates efficacy of immune checkpoint inhibitors. J Hematol Oncol. 2018;11(1):47. doi:10.1186/s13045-018-0592-6.
  • Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–pd-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97–103. doi:10.1126/science.aan4236.
  • Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti–pd-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104–108. doi:10.1126/science.aao3290.
  • Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of pd-1–based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–97. doi:10.1126/science.aan3706.
  • Jiang S, Geng S, Chen Q, Zhang C, Cheng M, Yu Y, Zhang S, Shi N, Dong M. Effects of concomitant antibiotics use on immune checkpoint inhibitor efficacy in cancer patients. Front Oncol. 2022;12(823705). doi:10.3389/fonc.2022.823705.
  • Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, Adler K, Dick-Necula D, Raskin S, Bloch N, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021;2021371(6529):602–609. doi:10.1126/science.abb5920.
  • Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin J-M, Morrison RM, Deblasio RN, Menna C, Ding Q, Pagliano O, et al. Fecal microbiota transplant overcomes resistance to anti–pd-1 therapy in melanoma patients. Science. 2021;2021371(6529):595–602. doi:10.1126/science.abf3363.
  • Borgers JSW, Burgers FH, Terveer EM, van Leerdam ME, Korse CM, Kessels R, Flohil CC, Blank CU, Schumacher TN, van Dijk M, et al. Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase ib/iia trial. BMC Cancer. 2022;22(1):1366. doi:10.1186/s12885-022-10457-y.