15,772
Views
100
CrossRef citations to date
0
Altmetric
Review

Lactate dehydrogenase: a marker of diminished antitumor immunity

, , , , , , & show all
Article: 1731942 | Received 15 Oct 2019, Accepted 12 Jan 2020, Published online: 26 Feb 2020

References

  • Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob -J-J, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1480–11. doi:10.1016/S1470-2045(18)30700-9.
  • Petrelli F, Ardito R, Merelli B, Lonati V, Cabiddu M, Seghezzi S, Barni S, Ghidini A. Prognostic and predictive role of elevated lactate dehydrogenase in patients with melanoma treated with immunotherapy and BRAF inhibitors: a systematic review and meta-analysis. Melanoma Res. 2019;29:1–12. doi:10.1097/CMR.0000000000000520.
  • Petrelli F, Cabiddu M, Coinu A, Borgonovo K, Ghilardi M, Lonati V, Barni S. Prognostic role of lactate dehydrogenase in solid tumors: A systematic review and meta-analysis of 76 studies. Acta Oncol (Madr). 2015;54:961–970. doi:10.3109/0284186X.2015.1043026.
  • Larkin J, Minor D, D’Angelo S, Neyns B, Smylie M, Miller WH, Gutzmer R, Linette G, Chmielowski B, Lao CD, et al. Overall survival in patients with advanced melanoma who received nivolumab versus investigator’s choice chemotherapy in checkMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018;36:383–390. doi:10.1200/JCO.2016.71.8023.
  • Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Hogg D, Hill A, Carlino MS, et al. 3303 efficacy and safety in key patient subgroups of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naïve patients with advanced melanoma (MEL) (CheckMate 067). Eur J Cancer. 2015;51:S664–S665. doi:10.1016/S0959-8049(16)31822-6.
  • Taniguchi Y, Tamiya A, Isa S-I, Nakahama K, Okishio K, Shiroyama T, Suzuki H, Inoue T, Tamiya M, Hirashima T, et al. Predictive factors for poor progression-free survival in patients with non-small cell lung cancer treated with nivolumab. Anticancer Res. 2017;37:5857–5862.
  • Inomata M, Hirai T, Seto Z, Tokui K, Taka C, Okazawa S, Kambara K, Ichikawa T, Imanishi S, Yamada T, et al. Clinical parameters for predicting the survival in patients with squamous and non-squamous-cell NSCLC receiving PD-1 inhibitor therapy. Pathol Oncol Res. 2018;474:569–575.
  • Oya Y, Yoshida T, Kuroda H, Mikubo M, Kondo C, Shimizu J, Horio Y, Sakao Y, Hida T, Yatabe Y. Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small-cell lung cancer. Oncotarget. 2017;8:103117–103128.
  • Mezquita L, Auclin E, Ferrara R, Charrier M, Remon J, Planchard D, Ponce S, Ares LP, Leroy L, Audigier-Valette C, et al. Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer. JAMA Oncol. 2018;4:351–357.
  • Bigot F, Castanon E, Baldini C, Hollebecque A, Carmona A, Postel-Vinay S, Angevin E, Armand J-P, Ribrag V, Aspeslagh S, et al. Prospective validation of a prognostic score for patients in immunotherapy phase I trials: the Gustave Roussy Immune Score (GRIm-Score). Eur J Cancer. 2017;84:212–218. doi:10.1016/j.ejca.2017.07.027.
  • Cona MS, Lecchi M, Cresta S, Damian S, Del Vecchio M, Necchi A, Poggi MM, Raggi D, Randon G, Ratta R, et al. Combination of Baseline LDH, performance status and age as integrated algorithm to identify solid tumor patients with higher probability of response to anti PD-1 and PD-L1 monoclonal antibodies. Cancers (Basel). 2019;11:223. doi:10.3390/cancers11020223.
  • Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545:60–65. doi:10.1038/nature22079.
  • Joseph RW, Elassaiss-Schaap J, Kefford R, Hwu W-J, Wolchok JD, Joshua AM, Ribas A, Hodi FS, Hamid O, Robert C, et al. Baseline tumor size is an independent prognostic factor for overall survival in patients with melanoma treated with pembrolizumab. Clin Cancer Res. 2018;24:4960–4967. doi:10.1158/1078-0432.CCR-18-3340.
  • Agarwala SS, Keilholz U, Gilles E, Bedikian AY, Wu J, Kay R, Stein CA, Itri LM, Suciu S, Eggermont AMM. LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951). Eur J Cancer. 2009;45:1807–1814. doi:10.1016/j.ejca.2009.04.016.
  • Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Trarbach T, Folprecht G, Shi MM, Lebwohl D, Jalava T, Laurent D, et al. Prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with PTK787/ZK 222584 (Vatalanib) antiangiogenic therapy. Clin Cancer Res. 2011;17:4892–4900. doi:10.1158/1078-0432.CCR-10-2918.
  • Dercle L, Ammari S, Champiat S, Massard C, Ferté C, Taihi L, Seban R-D, Aspeslagh S, Mahjoubi L, Kamsu-Kom N, et al. Rapid and objective CT scan prognostic scoring identifies metastatic patients with long-term clinical benefit on anti-PD-1/-L1 therapy. Eur J Cancer. 2016;65:33–42. doi:10.1016/j.ejca.2016.05.031.
  • Labiano S, Palazon A, Melero I. Immune response regulation in the tumor microenvironment by hypoxia. Semin Oncol. 2015;42:378–386. doi:10.1053/j.seminoncol.2015.02.009.
  • Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science (80-). 2010;330:1340–1344. doi:10.1126/science.1193494.
  • Kayser G, Kassem A, Sienel W, Schulte-Uentrop L, Mattern D, Aumann K, Stickeler E, Werner M, Passlick B, zur Hausen A. lactate-dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1. Diagn Pathol. 2010;5:22. doi:10.1186/1746-1596-5-22.
  • Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, Harris AL. Tumour and angiogenesis research group: lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer. 2003;89:877–885. doi:10.1038/sj.bjc.6601205.
  • Dong T, Liu Z, Xuan Q, Wang Z, Ma W, Zhang Q. Tumor LDH-A expression and serum LDH status are two metabolic predictors for triple negative breast cancer brain metastasis. Sci Rep. 2017;7:6069. doi:10.1038/s41598-017-06378-7.
  • Danner BC, Didilis VN, Wiemeyer S, Stojanovic T, Kitz J, Emmert A, Füzesi L, Schöndube FA. Long-term survival is linked to serum LDH and partly to tumour LDH-5 in NSCLC. Anticancer Res. 2010;30:1347–1351.
  • de Heer EC, Brouwers AH, Boellaard R, Sluiter WJ, Diercks GFH, Hospers GAP, de Vries EGE, Jalving M. Mapping heterogeneity in glucose uptake in metastatic melanoma using quantitative 18F-FDG PET/CT analysis. EJNMMI Res. 2018;8:101. doi:10.1186/s13550-018-0453-x.
  • Shan X, Wang D, Chen J, Xiao X, Jiang Y, Wang Y, Fan Y. Necrosis degree displayed in computed tomography images correlated with hypoxia and angiogenesis in breast cancer. J Comput Assist Tomogr. 2013;37:22–28. doi:10.1097/RCT.0b013e318279abd1.
  • Eustace A, Irlam JJ, Taylor J, Denley H, Agrawal S, Choudhury A, Ryder D, Ord JJ, Harris AL, Rojas AM, et al. Necrosis predicts benefit from hypoxia-modifying therapy in patients with high risk bladder cancer enrolled in a phase III randomised trial. Radiother Oncol. 2013;108:40–47. doi:10.1016/j.radonc.2013.05.017.
  • Bachmann IM, Ladstein RG, Straume O, Naumov GN, Akslen LA. Tumor necrosis is associated with increased alphavbeta3 integrin expression and poor prognosis in nodular cutaneous melanomas. BMC Cancer. 2008;8:362. doi:10.1186/1471-2407-8-362.
  • Bredholt G, Mannelqvist M, Stefansson IM, Birkeland E, Bø TH, Øyan AM, Trovik J, Kalland K-H, Jonassen I, Salvesen HB, et al. Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses. Oncotarget. 2015;6:39676–39691. doi:10.18632/oncotarget.v6i37.
  • Lewis JS, Landers RJ, Underwood JC, Harris ALLC:. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol. 2000;192:150–158. PubMed - NCBI. doi:10.1002/(ISSN)1096-9896.
  • Suzuki J, Kojima M, Aokage K, Sakai T, Nakamura H, Ohara Y, Tane K, Miyoshi T, Sugano M, Fujii S, et al. Clinicopathological characteristics associated with necrosis in pulmonary metastases from colorectal cancer. Virchows Arch. 2019;474:569–575. doi:10.1007/s00428-019-02535-7.
  • Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–257. doi:10.1038/35025220.
  • Milross CG, Tucker SL, Mason KA, Hunter NR, Peters LJ, Milas L. The effect of tumor size on necrosis and polarographically measured pO2. Acta Oncol. 1997;36:183–189. doi:10.3109/02841869709109228.
  • Serganova I, Rizwan A, Ni X, Thakur SB, Vider J, Russell J, Blasberg R, Koutcher JA. Metabolic imaging: a link between lactate dehydrogenase A, lactate, and tumor phenotype. Clin Cancer Res. 2011;17:6250–6261. doi:10.1158/1078-0432.CCR-11-0397.
  • Chang C-H, Curtis JD, Maggi LB, Faubert B, Villarino AV, O’Sullivan D, Huang S-C-C, van der Windt GJW, Blagih J, Qiu J, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 2013;153:1239–1251. doi:10.1016/j.cell.2013.05.016.
  • Chang C-H, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJW, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162:1229–1241. doi:10.1016/j.cell.2015.08.016.
  • Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24:657–671. doi:10.1016/j.cmet.2016.08.011.
  • Renner K, Geiselhöringer A-L, Fante M, Bruss C, Färber S, Schönhammer G, Peter K, Singer K, Andreesen R, Hoffmann P, et al. Metabolic plasticity of human T cells: preserved cytokine production under glucose deprivation or mitochondrial restriction, but 2-deoxy-glucose affects effector functions. Eur J Immunol. 2015;45:2504–2516. doi:10.1002/eji.v45.9.
  • Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ, Kopinski PK, Wang L, et al. Foxp3 Reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017; 25:1282–1293.e7.
  • Ratnikov BI, Scott DA, Osterman AL, Smith JW, Ronai ZA. Metabolic rewiring in melanoma. Oncogene. 2017;36:147–157. doi:10.1038/onc.2016.198.
  • Rizwan A, Serganova I, Khanin R, Karabeber H, Ni X, Thakur S, Zakian KL, Blasberg R, Koutcher JA. Relationships between LDH-A, lactate, and metastases in 4T1 breast tumors. Clin Cancer Res. 2013;19:5158–5169. doi:10.1158/1078-0432.CCR-12-3300.
  • Longo DL, Bartoli A, Consolino L, Bardini P, Arena F, Schwaiger M, Aime S. In vivo imaging of tumor metabolism and acidosis by combining PET and MRI-CEST pH imaging. Cancer Res. 2016;76:6463–6470. doi:10.1158/0008-5472.CAN-16-0825.
  • Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007;109:3812–3819. doi:10.1182/blood-2006-07-035972.
  • Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z, Xu C, Williams LJ, Wang Z, Bristow CA, Carugo A, et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 2018;27:977–987.e4. doi:10.1016/j.cmet.2018.02.024.
  • Husain Z, Huang Y, Seth P, Sukhatme VP. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J Immunol. 2013;191:1486–1495. doi:10.4049/jimmunol.1202702.
  • Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513:559–563. doi:10.1038/nature13490.
  • Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang L-P, Gimotty PA, Gilks CB, Lal P, Zhang L, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 2011;475:226–230. doi:10.1038/nature10169.
  • Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP, et al. Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci. 2012;109:E2784–E2793. doi:10.1073/pnas.1202366109.
  • Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, Johnson RS, Goldrath AW. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat Immunol. 2013;14:1173–1182. doi:10.1038/ni.2714.
  • Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol. 2016;29:90–96. doi:10.1016/j.coph.2016.06.009.
  • Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y, Movahedi K, Houbracken I, Schouppe E, Elkrim Y, et al. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res. 2014;74:24–30. doi:10.1158/0008-5472.CAN-13-1196.
  • Corzo CA, Condamine T, Lu L, Cotter MJ, Youn J-I, Cheng P, Cho H-I, Celis E, Quiceno DG, Padhya T, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207:2439–2453. doi:10.1084/jem.20100587.
  • Lacroix R, Rozeman EA, Kreutz M, Renner K, Blank CU. Targeting tumor-associated acidity in cancer immunotherapy. Cancer Immunol Immunother. 2018;67:1331–1348.
  • Kim H, Kwon HJ, Han YB, Park SY, Kim ES, Kim SH, Kim YJ, Lee JS, Chung JH. Increased CD3+ T cells with a low FOXP3+/CD8+ T cell ratio can predict anti-PD-1 therapeutic response in non-small cell lung cancer patients. Mod Pathol. 2019;32:367–375.
  • Martens A, Wistuba-Hamprecht K, Geukes Foppen MH, Yuan J, Postow MA, Wong P, Romano E, Khammari A, Dreno B, Capone M, et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res. 2016;22:2908–2918.
  • Weber J, Gibney G, Kudchadkar R, Yu B, Cheng P, Martinez AJ, Kroeger J, Richards A, Mccormick L, Moberg V, et al. Phase I/II study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab. Cancer Immunol Res. 2016;4:345–353.
  • Wood DC, Varela V, Palmquist M, Weber F. Serum lactic dehydrogenase and isoenzyme changes in clinical cancer. J Surg Oncol. 1973;5:251–257.
  • Diem S, Kasenda B, Spain L, Martin-Liberal J, Marconcini R, Gore M, Larkin J. Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. Br J Cancer. 2016;114:256–261.
  • Wagner NB, Forschner A, Leiter U, Garbe C, Eigentler TK. S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies. Br J Cancer. 2018;119:339–346.
  • Simeone E, Gentilcore G, Giannarelli D, Grimaldi AM, Caracò C, Curvietto M, Esposito A, Paone M, Palla M, Cavalcanti E, et al. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother. 2014;63:675–683.
  • Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
  • Katt WP, Cerione RA. Inhibition of cancer metabolism: a patent landscape. Pharm Pat Anal. 2019;8:117–138.
  • Zhang S-L, He Y, Tam KY. Targeting cancer metabolism to develop human lactate dehydrogenase (h LDH)5 inhibitors. Drug Discov Today. 2018;23:1407–1415.
  • Gottfried E, Lang SA, Renner K, Bosserhoff A, Gronwald W, Rehli M, Einhell S, Gedig I, Singer K, Seilbeck A, et al. New aspects of an old drug – diclofenac targets MYC and glucose metabolism in tumor cells. PLoS One. 2013;8(7):e66987. doi:10.1371/journal.pone.0066987.
  • Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, Cova A, Canese R, Jachetti E, Rossetti M, et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 2012;72:2746–2756.
  • Homicsko K, Richtig G, Tuchmann F, Tsourti Z, Hanahan D, Coukos G, Wind-Rotolo M, Richtig E, Zygoura P, Holler C, et al. LBA2Proton pump inhibitors negatively impact survival of PD-1 inhibitor based therapies in metastatic melanoma patients. Ann Oncol. 2018:29(Supp 10). doi:10.1093/annonc/mdy511.001.
  • Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, Tigchelaar EF, Jankipersadsing SA, Cenit MC, Harmsen HJM, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016;65:740–748.
  • Gong J, Chehrazi-Raffle A, Placencio-Hickok V, Guan M, Hendifar A, Salgia R. The gut microbiome and response to immune checkpoint inhibitors: preclinical and clinical strategies. Clin Transl Med. 2019;8(1):9.
  • Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, Damaghi M, Wojtkowiak JW, Mul JJ, Ibrahim-Hashim A, et al. Microenvironment and immunology neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 2016;76(6):1381–1390.
  • Long GV, Grob -J-J, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016;17:1743–1754.
  • Major P, Trarbach T, Lenz H, Kerr D, Pendergrass K, Douillard J, Chen B, Laurent D. Jacques C CE van: A meta-analysis of two randomized, double-blind, placebo-controlled, phase III studies in patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK/ZK to determine clinical benefit on progression-free survival (PFS) in high LDH pts. J Clin Oncol. 2006;24(Supp 18):3529.
  • Scartozzi M, Giampieri R, Maccaroni E, Del Prete M, Faloppi L, Bianconi M, Galizia E, Loretelli C, Belvederesi L, Bittoni A, et al. Pre-treatment lactate dehydrogenase levels as predictor of efficacy of first-line bevacizumab-based therapy in metastatic colorectal cancer patients. Br J Cancer. 2012;106:799–804.
  • Yin C, Jiang C, Liao F, Rong Y, Cai X, Guo G, Qiu H, Chen X, Zhang B, He W, et al. Initial LDH level can predict the survival benefit from bevacizumab in the first-line setting in Chinese patients with metastatic colorectal cancer. Onco Targets Ther. 2014;7:1415–1422.
  • Mizukami Y, Li J, Zhang X, Zimmer MA, Iliopoulos O, Chung DC. Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer. Cancer Res. 2004;64:1765–1772.
  • Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL. Tumour angiogenesis research group: lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway—a report of the tumour angiogenesis research group. J Clin Oncol. 2006;24:4301–4308.
  • Faloppi L, Del Prete M, Gardini AC, Santini D, Silvestris N, Bianconi M, Giampieri R, Valgiusti M, Brunetti O, Bittoni A, et al. The correlation between LDH serum levels and clinical outcome in advanced biliary tract cancer patients treated with first line chemotherapy. Sci Rep. 2016;6:24136.
  • Yi M, Jiao D, Qin S, Chu Q, Wu K, Li A. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer. 2019;18:60.
  • Horikawa N, Abiko K, Matsumura N, Hamanishi J, Baba T, Yamaguchi K, Yoshioka Y, Koshiyama M, Konishi I. Expression of vascular endothelial growth factor in ovarian cancer inhibits tumor immunity through the accumulation of myeloid-derived suppressor cells. Clin Cancer Res. 2017;23:587–599.
  • Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012;109:17561–17566.
  • Lin Z, Zhang Q, Luo W. Angiogenesis inhibitors as therapeutic agents in cancer: challenges and future directions. Eur J Pharmacol. 2016;793:76–81.
  • Yuan J, Zhou J, Dong Z, Tandon S, Kuk D, Panageas KS, Wong P, Wu X, Naidoo J, Page DB, et al. Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res. 2014;2:127–132.
  • Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, Zeng W, Giobbie-Hurder A, Atkins MB, Ibrahim N, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014;2:632–642.
  • Sheng X, Yan X, Chi Z, Si L, Cui C, Tang B, Li S, Mao L, Lian B, Wang X, et al. Axitinib in combination with toripalimab, a humanized immunoglobulin g4 monoclonal antibody against programmed cell death-1, in patients with metastatic mucosal melanoma: an open-label Phase IB trial. J Clin Oncol. 2019. doi:10.1200/JCO.19.00210.
  • McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, Fong L, Joseph RW, Pal SK, Reeves JA, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24:749–757.
  • Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116–1127.
  • Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103–1115.
  • Katsurada M, Nagano T, Tachihara M, Kiriu T, Furukawa K, Koyama K, Otoshi T, Sekiya R, Hazama D, Tamura D, et al. Baseline tumor size as a predictive and prognostic factor of immune checkpoint inhibitor therapy for non-small cell lung cancer. Anticancer Res. 2019;39:815–825.
  • Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18:1483–1492.
  • Zhang D, He W, Wu C, Tan Y, He Y, Xu B, Chen L, Li Q, Jiang J. Scoring system for tumor-infiltrating lymphocytes and its prognostic value for gastric cancer. Front Immunol. 2019;10:71.
  • König L, Mairinger FD, Hoffmann O, Bittner A-K, Schmid KW, Kimmig R, Kasimir-Bauer S, Bankfalvi A. Dissimilar patterns of tumor-infiltrating immune cells at the invasive tumor front and tumor center are associated with response to neoadjuvant chemotherapy in primary breast cancer. BMC Cancer. 2019;19:120.
  • Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39:782–795.
  • Wang B, Wu S, Zeng H, Liu Z, Dong W, He W, Chen X, Dong X, Zheng L, Lin T, et al. CD103 + tumor infiltrating lymphocytes predict a favorable prognosis in urothelial cell carcinoma of the bladder. J Urol. 2015;194:556–562.
  • Gao J, Karam JA, Tannir NM, Campbell MT, Slack Tidwell R, Ahrar K, Rao P, Ng CS, Jonasch E, Matin SF, et al. A pilot randomized study evaluating nivolumab (nivo) or nivo + bevacizumab (bev) or nivo + ipilimumab (ipi) in patients with metastatic renal cell carcinoma (MRCC) eligible for cytoreductive nephrectomy, metastasectomy or post-treatment biopsy (Bx). J Clin Oncol. 2019;37:4501.
  • Parmenter TJ, Kleinschmidt M, Kinross KM, Bond ST, Li J, Kaadige MR, Rao A, Sheppard KE, Hugo W, Pupo GM, et al. Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov. 2014;4:423–433.
  • Schadendorf D, Long GV, Stroiakovski D, Karaszewska B, Hauschild A, Levchenko E, Chiarion-Sileni V, Schachter J, Garbe C, Dutriaux C, et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer. 2017;82:45–55.
  • Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, Mitra D, Boni A, Newton LP, Liu C, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19:1225–1231.
  • Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365–1366.
  • Amin A, Lawson DH, Salama AKS, Koon HB, Guthrie T, Thomas SS, O’Day SJ, Shaheen MF, Zhang B, Francis S, et al. Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma. J Immunother Cancer. 2016;4:44.