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Review

Facing the future: challenges and opportunities in adoptive T cell therapy in cancer

, , , , , , , , ORCID Icon & show all
Pages 811-827 | Received 07 Jan 2019, Accepted 12 Apr 2019, Published online: 30 Apr 2019

References

  • Dudley ME, Gross CA, Somerville RP, et al. Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol. 2013;31:2152–2159.
  • Rosenberg SA, Yannelli JR, Yang JC, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994;86:1159–1166.
  • Goff SL, Dudley ME, Citrin DE, et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol. 2016;34:2389–2397.
  • Besser MJ, Shapira-Frommer R, Itzhaki O, et al. Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res off J Am Assoc Cancer Res. 2013;19:4792–4800.
  • Mehta GU, Malekzadeh P, Shelton T, et al. Outcomes of adoptive cell transfer with tumor-infiltrating lymphocytes for metastatic melanoma patients with and without brain metastases. J Immunother. 2018;41:241–247.
  • Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T cell transfer immunotherapy. Clin Cancer Res off J Am Assoc Cancer Res. 2011;17:4550–4557.
  • Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119:2709–2720.
  • Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–549.
  • Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–528.
  • Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314:126–129.
  • Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29:917–924.
  • Lu YC, Parker LL, Lu T, et al. Treatment of patients with metastatic cancer using a major histocompatibility complex class II-restricted T cell receptor targeting the cancer germline antigen MAGE-A3. J Clin Oncol. 2017;35:3322–3329.
  • Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–1639.
  • Hodi FS, O‘Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723.
  • Massard C, Gordon MS, Sharma S, et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34:3119–3125.
  • Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–918.
  • Gilham DE, Anderson J, Bridgeman JS, et al. Adoptive T cell therapy for cancer in the United kingdom: a review of activity for the British society of gene and cell therapy annual meeting 2015. Hum Gene Ther. 2015;26:276–285.
  • Andersen R, Donia M, Ellebaek E, et al. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated IL2 regimen. Clin Cancer Res off J Am Assoc Cancer Res. 2016;22:3734–3745.
  • Dudley ME, Wunderlich JR, Shelton TE, et al. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother. 2003;26:332–342.
  • Zhou J, Nagarkatti P, Zhong Y, et al. Characterization of T cell memory phenotype after in vitro expansion of tumor-infiltrating lymphocytes from melanoma patients. Anticancer Res. 2011;31:4099–4109.
  • Pockaj BA, Sherry RM, Wei JP, et al. Localization of 111 indium-labeled tumor infiltrating lymphocytes to tumor in patients receiving adoptive immunotherapy. Augmentation with cyclophosphamide and correlation with response. Cancer. 1994;73:1731–1737.
  • Klebanoff CA, Khong HT, Antony PA, et al. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26:111–117.
  • Marits P, Karlsson M, Sherif A, et al. Detection of immune responses against urinary bladder cancer in sentinel lymph nodes. Eur Urol. 2006;49:59–70.
  • Karlsson M, Marits P, Dahl K, et al. Pilot study of sentinel-node-based adoptive immunotherapy in advanced colorectal cancer. Ann Surg Oncol. 2010;17:1747–1757.
  • Sherif A, Hasan MN, Radecka E, et al. Pilot study of adoptive immunotherapy with sentinel node-derived T cells in muscle-invasive urinary bladder cancer. Scand J Urol. 2015;49:453–462.
  • Zhen YH, Liu XH, Yang Y, et al. Phase I/II study of adjuvant immunotherapy with sentinel lymph node T lymphocytes in patients with colorectal cancer. Cancer Immunol Immunother. 2015;64:1083–1093.
  • Rafiq S, Purdon TJ, Daniyan AF, et al. Optimized T cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular wilms tumor 1 antigen. Leukemia. 2017;31:1788–1797.
  • Valitutti S, Muller S, Cella M, et al. Serial triggering of many T cell receptors by a few peptide-MHC complexes. Nature. 1995;375:148–151.
  • Chmielewski M, Hombach AA, Abken H. CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T cell attack. Gene Ther. 2011;18:62–72.
  • Coulie PG, Van Den Eynde BJ, van der Bruggen P, et al. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer. 2014;14:135–146.
  • van der Bruggen P, Traversari C, Chomez P, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991;254:1643–1647.
  • Dembic Z, Haas W, Weiss S, et al. Transfer of specificity by murine alpha and beta T cell receptor genes. Nature. 1986;320:232–238.
  • Duval L, Schmidt H, Kaltoft K, et al. Adoptive transfer of allogeneic cytotoxic T lymphocytes equipped with a HLA-A2 restricted MART-1 T cell receptor: a phase I trial in metastatic melanoma. Clin Cancer Res off J Am Assoc Cancer Res. 2006;12:1229–1236.
  • Fournier C, Martin F, Zitvogel L, et al. Trial watch: adoptively transferred cells for anticancer immunotherapy. Oncoimmunology. 2017;6:e1363139.
  • Ping Y, Liu C, Zhang Y. T cell receptor-engineered T cells for cancer treatment: current status and future directions. Protein Cell. 2018;9:254–266.
  • Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344:641–645.
  • Adusumilli PS, Cherkassky L, Villena-Vargas J, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med. 2014;6:261ra151.
  • Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116:4099–4102.
  • June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379:64–73.
  • Ruella M, Maus MV. Catch me if you can: leukemia escape after CD19-directed T cell immunotherapies. Comput Struct Biotechnol J. 2016;14:357–362.
  • Zhao J, Song Y, Liu D. Clinical trials of dual-target CAR T cells, donor-derived CAR T cells, and universal CAR T cells for acute lymphoid leukemia. J Hematol Oncol. 2019;12:17.
  • Long KB, Young RM, Boesteanu AC, et al. CAR T cell therapy of non-hematopoietic malignancies: detours on the road to clinical success. Front Immunol. 2018;9:2740.
  • Paucek RD, Baltimore D, Li G. The cellular immunotherapy revolution: arming the immune system for precision therapy. Trends Immunol. 2019;40:292–309.
  • Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74.
  • Ward JP, Gubin MM, Schreiber RD. The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer. Adv Immunol. 2016;130:25–74.
  • Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–2028.
  • Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184–043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700–712.
  • Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017;18:1493–1501.
  • Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–2454.
  • Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–2520.
  • McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–1469.
  • Tran E, Robbins PF, Lu YC, et al. T cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med. 2016;375:2255–2262.
  • Paulson KG, Voillet V, McAfee MS, et al. Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA. Nat Commun. 2018;9:3868.
  • Marty R, Kaabinejadian S, Rossell D, et al. MHC-I genotype restricts the oncogenic mutational landscape. Cell. 2017;171:1272–1283 e1215.
  • Marty R, Thompson WK, Salem RM, et al. Evolutionary pressure against MHC class II binding cancer mutations. Cell. 2018;175:416–428 e413.
  • Choi M, Scholl UI, Ji W, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009;106:19096–19101.
  • Hundal J, Carreno BM, Petti AA, et al. pVAC-Seq: A genome-guided in silico approach to identifying tumor neoantigens. Genome Med. 2016;8:11.
  • Bjerregaard AM, Nielsen M, Hadrup SR, et al. MuPeXI: prediction of neo-epitopes from tumor sequencing data. Cancer Immunol Immunother. 2017;66:1123–1130.
  • Tappeiner E, Finotello F, Charoentong P, et al. TIminer: NGS data mining pipeline for cancer immunology and immunotherapy. Bioinformatics. 2017;33:3140–3141.
  • Castle JC, Kreiter S, Diekmann J, et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012;72:1081–1091.
  • Andreatta M, Nielsen M. Gapped sequence alignment using artificial neural networks: application to the MHC class I system. Bioinformatics. 2016;32:511–517.
  • Bassani-Sternberg M, Braunlein E, Klar R, et al. Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry. Nat Commun. 2016;7:13404.
  • Bassani-Sternberg M, Pletscher-Frankild S, Jensen LJ, et al. Mass spectrometry of human leukocyte antigen class I peptidomes reveals strong effects of protein abundance and turnover on antigen presentation. Mol Cell Proteomics. 2015;14:658–673.
  • Robbins PF, Lu YC, El-Gamil M, et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med. 2013;19:747–752.
  • Yadav M, Jhunjhunwala S, Phung QT, et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature. 2014;515:572–576.
  • Kreiter S, Vormehr M, van de Roemer N, et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature. 2015;520:692–696.
  • Liepe J, Marino F, Sidney J, et al. A large fraction of HLA class I ligands are proteasome-generated spliced peptides. Science. 2016;354:354–358.
  • Joseph CG, Darrah E, Shah AA, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science. 2014;343:152–157.
  • Kim S, Kim HS, Kim E, et al. Neopepsee: accurate genome-level prediction of neoantigens by harnessing sequence and amino acid immunogenicity information. Ann Oncol. 2018;29:1030–1036.
  • Stronen E, Toebes M, Kelderman S, et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science. 2016;352:1337–1341.
  • Yossef R, Tran E, Deniger DC, et al. Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy. JCI Insight. 2018;3(19).
  • Conlon KC, Miljkovic MD, Waldmann TA. Cytokines in the treatment of cancer. J Interferon Cytokine Res. 2019;39(1):6–21.
  • Wahid B, Ali A, Rafique S, et al. An overview of cancer immunotherapeutic strategies. Immunotherapy. 2018;10:999–1010.
  • Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. Jama. 1994;271:907–913.
  • Petrozziello E, Sturmheit T, Mondino A. Exploiting cytokines in adoptive T cell therapy of cancer. Immunotherapy. 2015;7:573–584.
  • Berger C, Jensen MC, Lansdorp PM, et al. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest. 2008;118:294–305.
  • Gattinoni L, Powell DJ Jr., Rosenberg SA, et al. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol. 2006;6:383–393.
  • Xu Y, Zhang M, Ramos CA, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood. 2014;123:3750–3759.
  • Zhou J, Shen X, Huang J, et al. Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J Iimmunol. 2005;175:7046–7052.
  • Dudley ME, Gross CA, Langhan MM, et al. CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin Cancer Res off J Am Assoc Cancer Res. 2010;16:6122–6131.
  • Ghassemi S, Nunez-Cruz S, O‘Connor RS, et al. Reducing ex vivo culture improves the antileukemic activity of Chimeric Antigen Receptor (CAR) T cells. Cancer Immunol Res. 2018;6:1100–1109.
  • Yang S, Gattinoni L, Liu F, et al. In vitro generated anti-tumor T lymphocytes exhibit distinct subsets mimicking in vivo antigen-experienced cells. Cancer Immunol Immunother. 2011;60:739–749.
  • Berglund S, Gertow J, Magalhaes I, et al. Cord blood T cells cultured with IL-7 in addition to IL-2 exhibit a higher degree of polyfunctionality and superior proliferation potential. J Immunother. 2013;36:432–441.
  • Chen Y, Sun C, Landoni E, et al. Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15. Clin Cancer Res off J Am Assoc Cancer Res. 2019.
  • Davis CC, Marti LC, Sempowski GD, et al. Interleukin-7 permits Th1/Tc1 maturation and promotes ex vivo expansion of cord blood T cells: a critical step toward adoptive immunotherapy after cord blood transplantation. Cancer Res. 2010;70:5249–5258.
  • Gargett T, Brown MP. Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2. Cytotherapy. 2015;17:487–495.
  • Ptackova P, Musil J, Stach M, et al. A new approach to CAR T cell gene engineering and cultivation using piggyBac transposon in the presence of IL-4, IL-7 and IL-21. Cytotherapy. 2018;20:507–520.
  • Ramos CA, Savoldo B, Torrano V, et al. Clinical responses with T lymphocytes targeting malignancy-associated kappa light chains. J Clin Invest. 2016;126:2588–2596.
  • Santegoets SJ, Turksma AW, Suhoski MM, et al. IL-21 promotes the expansion of CD27+ CD28+ tumor infiltrating lymphocytes with high cytotoxic potential and low collateral expansion of regulatory T cells. J Transl Med. 2013;11:37.
  • Wilkie S, Burbridge SE, Chiapero-Stanke L, et al. Selective expansion of chimeric antigen receptor-targeted T cells with potent effector function using interleukin-4. J Biol Chem. 2010;285:25538–25544.
  • Yang S, Ji Y, Gattinoni L, et al. Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails. Cancer Immunol Immunother. 2013;62:727–736.
  • Kaartinen T, Luostarinen A, Maliniemi P, et al. Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T cell expansion. Cytotherapy. 2017;19:689–702.
  • Zhang X, Lv X, Song Y. Short-term culture with IL-2 is beneficial for potent memory chimeric antigen receptor T cell production. Biochem Biophys Res Commun. 2018;495:1833–1838.
  • Boyman O, Krieg C, Homann D, et al. Homeostatic maintenance of T cells and natural killer cells. Cell Mol Life Sci. 2012;69:1597–1608.
  • Sportes C, Hakim FT, Memon SA, et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med. 2008;205:1701–1714.
  • Liu S, Riley J, Rosenberg S, et al. Comparison of common gamma-chain cytokines, interleukin-2, interleukin-7, and interleukin-15 for the in vitro generation of human tumor-reactive T lymphocytes for adoptive cell transfer therapy. J Immunother. 2006;29:284–293.
  • Kimura MY, Pobezinsky LA, Guinter TI, et al. IL-7 signaling must be intermittent, not continuous, during CD8⁺ T cell homeostasis to promote cell survival instead of cell death.. Nat Immunol. 2013;14:143–151.
  • van der Waart AB, van de Weem NM, Maas F, et al. Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy. Blood. 2014;124:3490–3500.
  • Carswell KS, Weiss JW, Papoutsakis ET. Low oxygen tension enhances the stimulation and proliferation of human T lymphocytes in the presence of IL-2. Cytotherapy. 2000;2:25–37.
  • Junker N, Thor Straten P, Andersen MH, et al. Characterization of ex vivo expanded tumor infiltrating lymphocytes from patients with malignant melanoma for clinical application. J Skin Cancer. 2011;2011:574695.
  • Becht E, Goc J, Germain C, et al. Shaping of an effective immune microenvironment to and by cancer cells. Cancer Immunol Immunother. 2014;63:991–997.
  • Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–1022.
  • Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science. 2013;339:1546–1558.
  • Rosenberg SA, Sherry RM, Morton KE, et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. J Iimmunol. 2005;175:6169–6176.
  • Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–998.
  • Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–296.
  • Khong HT, Restifo NP. Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol. 2002;3:999–1005.
  • Rodriguez JA. HLA-mediated tumor escape mechanisms that may impair immunotherapy clinical outcomes via T cell activation. Oncol Lett. 2017;14:4415–4427.
  • Kaplan DH, Shankaran V, Dighe AS, et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A. 1998;95:7556–7561.
  • Kearney CJ, Vervoort SJ, Hogg SJ, et al. Tumor immune evasion arises through loss of TNF sensitivity. Sci Immunol. 2018;3(23).
  • Schaaf MB, Garg AD, Agostinis P. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy. Cell Death Dis. 2018;9:115.
  • Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–598.
  • Welti J, Loges S, Dimmeler S, et al. Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Invest. 2013;123:3190–3200.
  • Swartz MA, Lund AW. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat Rev Cancer. 2012;12:210–219.
  • Chauhan VP, Martin JD, Liu H, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 2013;4:2516.
  • Lee JJ, Perera RM, Wang H, et al. Stromal response to hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci U S A. 2014;111:E3091–3100.
  • Wang-Gillam A. Targeting stroma: a tale of caution. J clin oncol. 2019;JCO1900056.
  • Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5:3–8.
  • Chouaib S, Noman MZ, Kosmatopoulos K, et al. Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer. Oncogene. 2017;36:439–445.
  • Noman MZ, Desantis G, Janji B, et al. PD-L1 is a novel direct target of HIF-1 alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781–790.
  • Motz GT, Santoro SP, Wang LP, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med. 2014;20:607–615.
  • Buckanovich RJ, Facciabene A, Kim S, et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med. 2008;14:28–36.
  • Hamzah J, Jugold M, Kiessling F, et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature. 2008;453:410–414.
  • Shrimali RK, Yu Z, Theoret MR, et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70:6171–6180.
  • Eil R, Vodnala SK, Clever D, et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature. 2016;537:539–543.
  • Shi J, Kantoff PW, Wooster R, et al. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17:20–37.
  • Parente-Pereira AC, Shmeeda H, Whilding LM, et al. Adoptive immunotherapy of epithelial ovarian cancer with Vgamma9V delta2 T cells, potentiated by liposomal alendronic acid. J Iimmunol. 2014;193:5557–5566.
  • Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964.
  • Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102:18538–18543.
  • Feig C, Jones JO, Kraman M, 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;110:20212–20217.
  • Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer. 2010;10:181–193.
  • Esbona K, Yi Y, Saha S, et al. The presence of cyclooxygenase 2, tumor-associated macrophages, and collagen alignment as prognostic markers for invasive breast carcinoma patients. Am J Pathol. 2018;188:559–573.
  • Shaashua L, Shabat-Simon M, Haldar R, et al. Perioperative COX-2 and beta-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial. Clin Cancer Res off J Am Assoc Cancer Res. 2017;23:4651–4661.
  • Arima K, Komohara Y, Bu L, et al. Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1 beta from activated macrophages leads to poor prognosis in pancreatic cancer. Cancer Sci. 2018;109:462–470.
  • Drew DA, Cao Y, Chan AT. Aspirin and colorectal cancer: the promise of precision chemoprevention. Nat Rev Cancer. 2016;16:173–186.
  • Zelenay S, van der Veen AG, Bottcher JP, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell. 2015;162:1257–1270.
  • Prima V, Kaliberova LN, Kaliberov S, et al. COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci U S A. 2017;114:1117–1122.
  • Wang J, Zhang L, Kang D, et al. Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulate the level of PD-1 in infiltrating CD8(+) T cells in patients with lung cancer. Oncol Lett. 2018;15:552–558.
  • Hamada T, Cao Y, Qian ZR, et al. Aspirin use and colorectal cancer survival according to tumor CD274 (programmed cell death 1 ligand 1) expression status. J Clin Oncol. 2017;35:1836–1844.
  • Legat A, Speiser DE, Pircher H, et al. Inhibitory receptor expression depends more dominantly on differentiation and activation than “exhaustion” of human CD8 T cells. Front Immunol. 2013;4:455.
  • Hahn AW, Gill DM, Pal SK, et al. The future of immune checkpoint cancer therapy after PD-1 and CTLA-4. Immunotherapy. 2017;9:681–692.
  • Bengsch B, Ohtani T, Khan O, et al. Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells. Immunity. 2018;48:1029-+.
  • Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–499.
  • Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8(+) T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29–37.
  • Wang X, Teng F, Kong L, et al. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023–5039.
  • Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.
  • Burr ML, Sparbier CE, Chan YC, et al. CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature. 2017;549:101–105.
  • Mezzadra R, Sun C, Jae LT, et al. Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature. 2017;549:106-+.
  • Daud AI, Wolchok JD, Robert C, et al. Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol. 2016;34:4102–4109.
  • Mougiakakos D, Choudhury A, Lladser A, et al. Regulatory T cells in cancer. Adv Cancer Res. 2010;107:57–117.
  • Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27:109–118.
  • Takeuchi Y, Nishikawa H. Roles of regulatory T cells in cancer immunity. Int Immunol. 2016;28:401–409.
  • Sugiyama D, Nishikawa H, Maeda Y, et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci U S A. 2013;110:17945–17950.
  • Keskinov AA, Shurin MR. Myeloid regulatory cells in tumor spreading and metastasis. Immunobiology. 2015;220:236–242.
  • Fujimura T, Mahnke K, Enk AH. Myeloid derived suppressor cells and their role in tolerance induction in cancer. J Dermatol Sci. 2010;59:1–6.
  • Molon B, Ugel S, Del Pozzo F, et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med. 2011;208:1949–1962.
  • Degroote H, Van Dierendonck A, Geerts A, et al. Preclinical and clinical therapeutic strategies affecting tumor-associated macrophages in hepatocellular carcinoma. J Immunol Res. 2018;2018:7819520.
  • Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–555.
  • Chanmee T, Ontong P, Konno K, et al. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014;6:1670–1690.
  • Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74:5057–5069.
  • Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov. 2018;17:887–904.
  • Li M, Knight DA, LAS, Smyth MJ, et al. A role for CCL2 in both tumor progression and immunosurveillance. Oncoimmunology. 2013;2:e25474.
  • Cassetta L, Kitamura T. Macrophage targeting: opening new possibilities for cancer immunotherapy. Immunology. 2018;155:285–293.
  • Rodell CB, Arlauckas SP, Cuccarese MF, et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat Biomed Eng. 2018;2:578–588.
  • Linette GP, Stadtmauer EA, Maus MV, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122:863–871.
  • Morgan RA, Chinnasamy N, Abate-Daga D, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013;36:133–151.
  • Border EC, Sanderson JP, Weissensteiner T, et al. Affinity-enhanced T cell receptors for adoptive T cell therapy targeting MAGE-A10: strategy for selection of an optimal candidate. Oncoimmunology. 2019;8:e1532759.
  • Kisielow J, Obermair FJ, Kopf M. Deciphering CD4(+) T cell specificity using novel MHC-TCR chimeric receptors. Nat Immunol. 2019;20(5):652–662.