A review of mechanisms of resistance to immune checkpoint inhibitors and potential strategies for therapy

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer over the last decade, bringing about a paradigm shift in systemic cancer therapy away from traditional cytotoxic and targeted therapies. While some patients have dramatic treatment responses, it is sobering to note that most tumors are either resistant at the outset, or develop resistance after initial response. A major area of translational and clinical research is in identifying therapeutic strategies to overcome resistance to ICIs. We have performed an in-depth review of the different mechanisms of resistance and potential avenues to overcome resistance through rationally designed combination treatment with ICIs.

Keywords

Immunotherapy resistance / tumor microenvironment / PD-1 / PD-L1 / CTLA-4

References

[1] Sharma P,Wargo JA.Primary, Adaptive, and acquired resistance to cancer immunotherapy..Cell2017;168:707-23 PMCID:PMC5391692

[2] Wei SC,Allison JP.Fundamental mechanisms of immune checkpoint blockade therapy..Cancer Discov2018;8:1069-86

[3] Coley WB.Contribution to the Knowledge of Sarcoma..Ann Surg1891;14:199-220 PMCID:PMC1428624

[4] Hoption Cann SA,van Netten C.Dr William coley and tumour regression: a place in history or in the future..Postgrad Med J2003;79:672-80 PMCID:PMC1742910

[5] Ribas A.Cancer immunotherapy using checkpoint blockade..Science2018;359:1350-5

[6] Fares CM,Drake CG,Hu-Lieskovan S.Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients?.Am Soc Clin Oncol Educ Book2019;39:147-64

[7] De Sousa Linhares A,Grabmeier-Pfistershammer K.Not all immune checkpoints are created equal..Front Immunol2018;9:1909 PMCID:PMC6127213

[8] Brunet JF,Luciani MF,Suzan M.A new member of the immunoglobulin superfamily--CTLA-4..Nature1987;328:267-70

[9] Krummel MF.CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation..J Exp Med1995;182:459-65 PMCID:PMC2192127

[10] Ishida Y,Shibahara K.Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death..EMBO J1992;11:3887-95 PMCID:PMC556898

[11] Iwai Y,Tanaka Y,Honjo T.Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade..Proc Natl Acad Sci U S A2002;99:12293-7 PMCID:PMC129438

[12] Strome SE,Tamura H,Flies DB.B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma..Cancer Res2003;63:6501-5

[13] Hirano F,Tamura H,Wang S.Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity..Cancer Res2005;65:1089-96

[14] Lipson EJ.Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma..Clin Cancer Res2011;17:6958-62 PMCID:PMC3575079

[15] Sambi M,Szewczuk MR.Current challenges in cancer immunotherapy: multimodal approaches to improve efficacy and patient response rates..J Oncol2019;2019:4508794 PMCID:PMC6420990

[16] Syn NL,Mok TSK.De-novo and acquired resistance to immune checkpoint targeting..Lancet Oncol2017;18:e731-41

[17] Jenkins RW,Flaherty KT.Mechanisms of resistance to immune checkpoint inhibitors..Br J Cancer2018;118:9-16 PMCID:PMC5765236

[18] Gide TN,Scolyer RA.Primary and acquired resistance to immune checkpoint inhibitors in metastatic melanoma..Clin Cancer Res2018;24:1260-70

[19] Gubin MM,Schuster H,Ward JP.Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens..Nature2014;515:577-81 PMCID:PMC4279952

[20] Schumacher TN.Neoantigens in cancer immunotherapy..Science2015;348:69-74

[21] Nowicki TS,Ribas A.Mechanisms of resistance to PD-1 and PD-L1 blockade..Cancer J2018;24:47-53 PMCID:PMC5785093

[22] Rizvi NA,Snyder A,Makarov V.Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer..Science2015;348:124-8 PMCID:PMC4993154

[23] van Rooij N,Philips D,Toebes M.Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma..J Clin Oncol2013;31:e439-42 PMCID:PMC3836220

[24] Le DT,Smith KN,Bartlett BR.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade..Science2017;357:409-13 PMCID:PMC5576142

[25] de Velasco G,Voss MH,Hsieh JJ.Tumor mutational load and immune parameters across metastatic renal cell carcinoma risk groups..Cancer Immunol Res2016;4:820-2 PMCID:PMC5050137

[26] Llosa NJ,Tam A,Hechenbleikner EM.The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints..Cancer Discov2015;5:43-51 PMCID:PMC4293246

[27] Neefjes J,Paul P.Towards a systems understanding of MHC class I and MHC class II antigen presentation..Nat Rev Immunol2011;11:823-36

[28] Marincola FM,Hicklin DJ.Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance..Adv Immunol2000;74:181-273

[29] Sucker A,Real B,Bielefeld N.Genetic evolution of T-cell resistance in the course of melanoma progression..Clin Cancer Res2014;20:6593-604

[30] Rooney MS,Wu CJ,Hacohen N.Molecular and genetic properties of tumors associated with local immune cytolytic activity..Cell2015;160:48-61 PMCID:PMC4856474

[31] Zhao F,Horn S,Bielefeld N.Melanoma lesions independently acquire T-cell resistance during metastatic latency..Cancer Res2016;76:4347-58

[32] Zaretsky JM,Shin DS,Hugo W.Mutations associated with acquired resistance to PD-1 blockade in melanoma..N Engl J Med2016;375:819-29 PMCID:PMC5007206

[33] Sade-Feldman M,Chen JH,Barzily-Rokni M.Resistance to checkpoint blockade therapy through inactivation of antigen presentation..Nat Commun2017;8:1136 PMCID:PMC5656607

[34] Pereira C,Pros E,Moro M.Genomic profiling of patient-derived xenografts for lung cancer identifies B2M inactivation impairing immunorecognition..Clin Cancer Res2017;23:3203-13

[35] Le DT,Wang H,Kemberling H.PD-1 Blockade in Tumors with Mismatch-Repair Deficiency..N Engl J Med2015;372:2509-20 PMCID:PMC4481136

[36] Dudley JC,Le DT.Microsatellite Instability as a Biomarker for PD-1 Blockade..Clin Cancer Res2016;22:813-20

[37] Karpf AR.Reactivating the expression of methylation silenced genes in human cancer..Oncogene2002;21:5496-503

[38] Kim HJ.Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs..Am J Transl Res2011;3:166-79 PMCID:PMC3056563

[39] Yoshihama S,Downs I,Vijayan S.NLRC5/MHC class I transactivator is a target for immune evasion in cancer..Proc Natl Acad Sci U S A2016;113:5999-6004 PMCID:PMC4889388

[40] Burr ML,Chan KL,Kersbergen A.An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer..Cancer Cell2019;36:385-401.e8 PMCID:PMC6876280

[41] Dunn GP,Old LJ.IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression..Cancer Res2005;65:3447-53

[42] Heninger E,Lang JM.Augmenting antitumor immune responses with epigenetic modifying agents..Front Immunol2015;6:29 PMCID:PMC4316783

[43] Li X,Chen M,Liu Y.Increased IFNγ⁺ T cells are responsible for the clinical responses of low-dose DNA-demethylating agent decitabine antitumor therapy..Clin Cancer Res2017;23:6031-43

[44] Ghoneim HE,Moustaki A,Dash P.De Novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation..Cell2017;170:142-57.e19 PMCID:PMC5568784

[45] Terracina KP,Payne KK,Baek A.DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer..Cancer Immunol Immunother2016;65:1061-73 PMCID:PMC4996686

[46] Shen L,Ramakrishnan S,Ellis L.Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models..PLoS One2012;7:e30815 PMCID:PMC3267747

[47] Orillion A,Damayanti N,Adelaiye-Ogala R.Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma..Clin Cancer Res2017;23:5187-201 PMCID:PMC5723438

[48] Christmas BJ,Hopkins AC,Ma HS.Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs..Cancer Immunol Res2018;6:1561-77 PMCID:PMC6279584

[49] Agarwala SS,Johnson ML,Gabrilovich D.Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma progressing on or after a PD-1/L1 blocking antibody..J Clin Oncol2018;36:9530

[50] Sullivan RJ,Johnson ML,Ordentlich P.Abstract CT072: efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma previously treated with anti-PD1 therapy..Cancer Res2019;79:CT072

[51] Hellmann M,Opyrchal M,Raez L.Efficacy/Safety of Entinostat (ENT) and Pembrolizumab (PEMBRO) in NSCLC patients previously treated with anti-PD-(L)1 therapy..J Thorac Oncol2018;13:S330

[52] Gray JE,Tanvetyanon T,Creelan B.Phase I/Ib study of pembrolizumab plus vorinostat in advanced/metastatic non-small cell lung cancer..Clin Cancer Res2019;25:6623-32 PMCID:PMC7234799

[53] Kalbasi A.Tumour-intrinsic resistance to immune checkpoint blockade..Nat Rev Immunol2020;20:25-39

[54] Spranger S,Gajewski TF.Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity..Nature2015;523:231-5

[55] Molina JR.The Ras/Raf/MAPK pathway..J Thorac Oncol2006;1:7-9

[56] Zhao X.Oncogenic pathways that affect antitumor immune response and immune checkpoint blockade therapy..Pharmacol Ther2018;181:76-84

[57] Liu C,Xu C,Zhang M.BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice..Clin Cancer Res2013;19:393-403 PMCID:PMC4120472

[58] Chen N,Zhan J,Tang Y.Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation..J Thorac Oncol2015;10:910-23

[59] Ota K,Kawahara A,Iwama E.Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer..Clin Cancer Res2015;21:4014-21

[60] Sumimoto H,Teramoto K.RAS-mitogen-activated protein kinase signal is required for enhanced PD-L1 expression in human lung cancers..PLoS One2016;11:e0166626 PMCID:PMC5112979

[61] Donia M,Nicoletti F,Hogdall E.BRAF inhibition improves tumor recognition by the immune system: potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer..Oncoimmunology2012;1:1476-83 PMCID:PMC3525603

[62] Loi S,Beavis PA,Denkert C.RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors..Clin Cancer Res2016;22:1499-509 PMCID:PMC4794351

[63] Liu L,Eastman S,Yadavilli S.The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4..Clin Cancer Res2015;21:1639-51

[64] Cantley LC.The phosphoinositide 3-kinase pathway..Science2002;296:1655-7

[65] Peng W,Hwu P.Complementing T-cell function: an inhibitory role of the complement system in T-cell-mediated antitumor immunity..Cancer Discov2016;6:953-5 PMCID:PMC6069599

[66] George S,Demetri GD,Rodig SJ.Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma..Immunity2017;46:197-204 PMCID:PMC5408320

[67] Zhan T,Boutros M.Wnt signaling in cancer..Oncogene2017;36:1461-73 PMCID:PMC5357762

[68] Luke JJ,Sweis RF,Gajewski TF.WNT/beta-catenin pathway activation correlates with immune exclusion across human cancers..Clin Cancer Res2019;25:3074-83 PMCID:PMC6522301

[69] Benci JL,Qiu Y,Dada H.Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade..Cell2016;167:1540-54.e12 PMCID:PMC5385895

[70] Gao J,Zhao H,Xiong L.Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to Anti-CTLA-4 therapy..Cell2016;167:397-404.e9 PMCID:PMC5088716

[71] Shin DS,Escuin-Ordinas H,Hu-Lieskovan S.Primary resistance to PD-1 blockade mediated by JAK1/2 mutations..Cancer Discov2017;7:188-201 PMCID:PMC5296316

[72] Woo SR,Corrales L,Furdyna MJ.STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors..Immunity2014;41:830-42 PMCID:PMC4384884

[73] Corrales L.Molecular pathways: targeting the stimulator of interferon genes (STING) in the immunotherapy of cancer..Clin Cancer Res2015;21:4774-9 PMCID:PMC4750108

[74] Corrales L,McWhirter SM,Sivick KE.Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity..Cell Rep2015;11:1018-30 PMCID:PMC4440852

[75] Fu J,Leong M,McWhirter SM.STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade..Sci Transl Med2015;7:283ra52 PMCID:PMC4504692

[76] Ager CR,Nicholas C,Jaiswal AR.Intratumoral STING activation with T-cell checkpoint modulation generates systemic antitumor immunity..Cancer Immunol Res2017;5:676-84 PMCID:PMC5547907

[77] Rivera Vargas T,Apetoh L.Rationale for stimulator of interferon genes-targeted cancer immunotherapy..Eur J Cancer2017;75:86-97 PMCID:PMC5362072

[78] Ohkuri T,Kosaka A,Ikeura M.STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment..Cancer Immunol Res2014;2:1199-208 PMCID:PMC4258479

[79] Koshy ST,Gu L,Mooney DJ.Liposomal delivery enhances immune activation by STING agonists for cancer immunotherapy..Adv Biosyst2017;1:1600013 PMCID:PMC6152940

[80] Wilson DR,Sunshine JC,Green JJ.Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy..Nanomedicine2018;14:237-46 PMCID:PMC6035751

[81] Challa SV,Sheri A,Meher G.Preclinical studies of SB 11285, a novel STING agonist for immuno-oncology..J Clin Oncol2017;35:e14616

[82] Ricklefs FL,Krenzlin H,Speranza MC.Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles..Sci Adv2018;4:eaar2766 PMCID:PMC5842038

[83] Theodoraki MN,Hoffmann TK,Whiteside TL.Clinical significance of PD-L1(+) exosomes in plasma of head and neck cancer patients..Clin Cancer Res2018;24:896-905 PMCID:PMC6126905

[84] Chen G,Zhang W,Wu M.Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response..Nature2018;560:382-6 PMCID:PMC6095740

[85] Poggio M,Pai CC,Belair CD.Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory..Cell2019;177:414-27.e13 PMCID:PMC6499401

[86] Rudensky AY.Regulatory T cells and Foxp3..Immunol Rev2011;241:260-8 PMCID:PMC3077798

[87] Sakaguchi S,Nomura T.Regulatory T cells and immune tolerance..Cell2008;133:775-87

[88] Liston A.Homeostatic control of regulatory T cell diversity..Nat Rev Immunol2014;14:154-65

[89] Setoguchi R,Takahashi T.Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization..J Exp Med2005;201:723-35 PMCID:PMC2212841

[90] Takahashi T,Yamazaki S,Shimizu J.Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4..J Exp Med2000;192:303-10 PMCID:PMC2193248

[91] Cao X,Fehniger TA,Collins LI.Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance..Immunity2007;27:635-46

[92] Fridman WH,Sautes-Fridman C.The immune contexture in human tumours: impact on clinical outcome..Nat Rev Cancer2012;12:298-306

[93] Hamid O,Nissan A,Aamdal S.A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma..J Transl Med2011;9:204 PMCID:PMC3239318

[94] Simpson TR,Montalvo-Ortiz W,Bergerhoff K.Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma..J Exp Med2013;210:1695-710 PMCID:PMC3754863

[95] Ha D,Kibayashi T,Sugiyama D.Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody..Proc Natl Acad Sci U S A2019;116:609-18 PMCID:PMC6329979

[96] Arce Vargas F,Litchfield K,Rosenthal R.Fc effector function contributes to the activity of human anti-CTLA-4 antibodies..Cancer Cell2018;33:649-63.e4 PMCID:PMC5904288

[97] Sharma N,Allison JP.TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion..Proc Natl Acad Sci U S A2019;116:10453-62 PMCID:PMC6534983

[98] Heath DJ,Cheng X,Prideaux M.An osteoprotegerin-like peptidomimetic inhibits osteoclastic bone resorption and osteolytic bone disease in myeloma..Cancer Res2007;67:202-8

[99] Bronte V,Overwijk WW,Pericle F.Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells..J Immunol1998;161:5313-20 PMCID:PMC2239007

[100] Yang L,Fukuda K,Green-Jarvis B.Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis..Cancer Cell2004;6:409-21

[101] Meyer C,Costa-Nunes CM,Montandon N,Michielin O,Speiser DE.Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab..Cancer Immunol Immunother2014;63:247-57

[102] de Coana YP,Poschke I,Yang Y.Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma..Oncotarget2017;8:21539-53 PMCID:PMC5400604

[103] Kaneda MM,Ralainirina N,Leem CJ.PI3Kgamma is a molecular switch that controls immune suppression..Nature2016;539:437-42 PMCID:PMC5479689

[104] Foubert P,Varner JA.PI3Kgamma activates integrin alpha4 and promotes immune suppressive myeloid cell polarization during tumor progression..Cancer Immunol Res2017;5:957-68 PMCID:PMC6422969

[105] Davis RJ,Clavijo PE,Cash H.Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kdelta/gamma..Cancer Res2017;77:2607-19 PMCID:PMC5466078

[106] Wiezorek J,Graves J.Death receptor agonists as a targeted therapy for cancer..Clin Cancer Res2010;16:1701-8

[107] Mirza N,Fricke I,Neuger AM.All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients..Cancer Res2006;66:9299-307 PMCID:PMC1586106

[108] Adamson PC,Finklestein JZ,Berg SL.Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-alpha2a in pediatric patients with refractory cancer..J Clin Oncol1997;15:3330-7

[109] Kusmartsev S,Yu B,Sotomayor E.All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination..Cancer Res2003;63:4441-9

[110] Tobin RP,Robinson WA,Borges VF.Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab..Int Immunopharmacol2018;63:282-91 PMCID:PMC6134177

[111] Karnes JH,Shaffer CM,Xu Y.Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants..Sci Transl Med2017;9: PMCID:PMC5563969

[112] Scala S.Molecular pathways: targeting the CXCR4-CXCL12 axis--untapped potential in the tumor microenvironment..Clin Cancer Res2015;21:4278-85

[113] Burger JA.CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment..Blood2006;107:1761-7

[114] Hughes R,Rowan C,Keklikoglou I.Perivascular M2 macrophages stimulate tumor relapse after chemotherapy..Cancer Res2015;75:3479-91 PMCID:PMC5024531

[115] Zhu Y,Meyer MA,West BL.CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models..Cancer Res2014;74:5057-69 PMCID:PMC4182950

[116] Mok S,Tsui C,Robert L.Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy..Cancer Res2014;74:153-61 PMCID:PMC3947337

[117] Gordon SR,Dulken BW,George BM.PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity..Nature2017;545:495-9 PMCID:PMC5931375

[118] Gibney GT,Atkins MB.Predictive biomarkers for checkpoint inhibitor-based immunotherapy..The Lancet Oncology2016;17:e542-51 PMCID:PMC5702534

[119] Tumeh PC,Yearley JH,Taylor EJ.PD-1 blockade induces responses by inhibiting adaptive immune resistance..Nature2014;515:568-71 PMCID:PMC4246418

[120] Goff SL,Citrin DE,Wunderlich JR.Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma..J Clin Oncol2016;34:2389-97 PMCID:PMC4981979

[121] Wei F,Ma Z,Medvec A.Strength of PD-1 signaling differentially affects T-cell effector functions..Proc Natl Acad Sci U S A2013;110:E2480-9 PMCID:PMC3703988

[122] Garon EB,Hui R,Balmanoukian AS.Pembrolizumab for the treatment of non-small-cell lung cancer..N Engl J Med2015;372:2018-28

[123] Patel SP.PD-L1 expression as a predictive biomarker in cancer immunotherapy..Mol Cancer Ther2015;14:847-56

[124] Blank CU,Held W,Kallies A.Defining ‘T cell exhaustion’..Nat Rev Immunol2019;19:665-74 PMCID:PMC7286441

[125] Miller BC,Al Abosy R,Virkud YV.Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade..Nat Immunol2019;20:326-36 PMCID:PMC6673650

[126] Siddiqui I,Chennupati V,Calderon-Copete S.Intratumoral Tcf1(+)PD-1(+)CD8(+) T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy..Immunity2019;50:195-211.e10

[127] Khan O,McDonald S,Ngiow SF.TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion..Nature2019;571:211-8 PMCID:PMC6713202

[128] Ribas A,Zaretsky J,Cornish A.PD-1 blockade expands intratumoral memory t cells..Cancer Immunol Res2016;4:194-203 PMCID:PMC4775381

[129] Horn LA,Palena C.Tumor plasticity and resistance to immunotherapy..Trends Cancer2020;6:432-41 PMCID:PMC7192950

[130] Zheng X,Kim J,Kaye J.Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer..Nature2015;527:525-30 PMCID:PMC4849281

[131] Fischer KR,Lee S,Li F.Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance..Nature2015;527:472-6 PMCID:PMC4662610

[132] Byers LA,Wang J,Girard L.An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance..Clin Cancer Res2013;19:279-90 PMCID:PMC3567921

[133] Waugh DJ.The interleukin-8 pathway in cancer..Clin Cancer Res2008;14:6735-41

[134] Cheng Y,Wei YQ.Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases..Biochim Biophys Acta Rev Cancer2019;1871:289-312

[135] Gregory PA,Smith E,Wright JA.An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition..Mol Biol Cell2011;22:1686-98 PMCID:PMC3093321

[136] Mariathasan S,Nickles D,Yuen K.TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells..Nature2018;554:544-8 PMCID:PMC6028240

[137] Tauriello DVF,Stork D,Badia-Ramentol J.TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis..Nature2018;554:538-43

[138] Massague J.TGFbeta signalling in context..Nat Rev Mol Cell Biol2012;13:616-30 PMCID:PMC4027049

[139] Pickup M,Moses HL.The roles of TGFbeta in the tumour microenvironment..Nat Rev Cancer2013;13:788-99 PMCID:PMC4025940

[140] Dodagatta-Marri E,Reeves MQ,To MD.α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas..J Immunother Cancer2019;7:62 PMCID:PMC6399967

[141] Knudson KM,Luo X,Schlom J.M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine..Oncoimmunology2018;7:e1426519 PMCID:PMC5927523

[142] Lan Y,Xu C,Marelli B.Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β..Sci Transl Med2018;10:eaan5488

[143] Strauss J,Schlom J,Cao L.Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFβ, in advanced solid tumors..Clin Cancer Res2018;24:1287-95

[144] Paolino M.The role of TAM family receptors in immune cell function: implications for cancer therapy..Cancers (Basel)2016;8: PMCID:PMC5082387

[145] Aguilera TA.Molecular Pathways: Oncologic pathways and their role in T-cell exclusion and immune evasion-a new role for the AXL receptor tyrosine kinase..Clin Cancer Res2017;23:2928-33 PMCID:PMC5474155

[146] Hamilton DH,Jales A,Fernando RI.Immunological targeting of tumor cells undergoing an epithelial-mesenchymal transition via a recombinant brachyury-yeast vaccine..Oncotarget2013;4:1777-90 PMCID:PMC3858563

[147] Heery CR,Rauckhorst M,Donahue RN.Phase I trial of a yeast-based therapeutic cancer vaccine (GI-6301) targeting the transcription factor brachyury..Cancer Immunol Res2015;3:1248-56 PMCID:PMC4636967

[148] Heery CR,McMahon S,Lepone LM.Phase I study of a poxviral TRICOM-based vaccine directed against the transcription factor brachyury..Clin Cancer Res2017;23:6833-45 PMCID:PMC5690815

[149] Gatti-Mays ME,Donahue RN,Madan RA.A phase I trial using a multitargeted recombinant adenovirus 5 (CEA/MUC1/Brachyury)-based immunotherapy vaccine regimen in patients with advanced cancer..Oncologist2019; PMCID:PMC7288633

[150] van Kooten C.CD40-CD40 ligand..J Leukoc Biol2000;67:2-17

[151] Byrne KT.CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer..Cell Rep2016;15:2719-32 PMCID:PMC4917417

[152] Vonderheide RH,Khalil M,Bajor DL.Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody..J Clin Oncol2007;25:876-83

[153] Croft M.Control of immunity by the TNFR-related molecule OX40 (CD134)..Annu Rev Immunol2010;28:57-78 PMCID:PMC2882161

[154] Curti BD,Morris N,Chisholm L.OX40 is a potent immune-stimulating target in late-stage cancer patients..Cancer Res2013;73:7189-98 PMCID:PMC3922072

[155] Sugamura K,Weinberg AD.Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40..Nat Rev Immunol2004;4:420-31

[156] Redmond WL,Kasiewicz MJ.Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity..Cancer Immunol Res2014;2:142-53 PMCID:PMC4007342

[157] Topalian SL,Pardoll DM.Immune checkpoint blockade: a common denominator approach to cancer therapy..Cancer Cell2015;27:450-61 PMCID:PMC4400238

[158] Fourcade J,Benallaoua M,Luescher IF.Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients..J Exp Med2010;207:2175-86 PMCID:PMC2947081

[159] Thommen DS,Muller P,Roller A.Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors..Cancer Immunol Res2015;3:1344-55

[160] Granier C,Combe P,Urien S.Tim-3 expression on tumor-infiltrating PD-1(+)CD8(+) T cells correlates with poor clinical outcome in renal cell carcinoma..Cancer Res2017;77:1075-82

[161] Johnston RJ,Hackney J,Huseni M.The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function..Cancer Cell2014;26:923-37

[162] Kurtulus S,Ngiow SF,Tan DJ.TIGIT predominantly regulates the immune response via regulatory T cells..J Clin Invest2015;125:4053-62 PMCID:PMC4639980

[163] Solomon BL.TIGIT: a novel immunotherapy target moving from bench to bedside..Cancer Immunol Immunother2018;67:1659-67

[164] Liu W,Zhang G,Cui Y.Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node..J Biol Chem2004;279:18748-58

[165] Kouo T,Pucsek AB,Solt S.Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells..Cancer Immunol Res2015;3:412-23 PMCID:PMC4390508

[166] Jha V,McGaha TL,Vas J.Lymphocyte activation gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity..PLoS One2014;9:e104484 PMCID:PMC4133201

[167] Ascierto PA,Bhatia S,Nyakas MS.LBA18Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti-PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations..Ann Oncol2017;28:

[168] Chon SY,Gupta SL.Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response elements in interferon-gamma-inducible expression of human indoleamine 2,3-dioxygenase gene..J Biol Chem1996;271:17247-52

[169] Yentz S.Indoleamine 2,3-Dioxygenase (IDO) Inhibition as a strategy to augment cancer immunotherapy..BioDrugs2018;32:311-7

[170] Smith C,Parker KH,DuHadaway JB.IDO is a nodal pathogenic driver of lung cancer and metastasis development..Cancer Discov2012;2:722-35 PMCID:PMC3677576

[171] Beatty GL,Clark J,Bowman KJ.First-in-Human Phase I study of the oral inhibitor of indoleamine 2,3-Dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies..Clin Cancer Res2017;23:3269-76 PMCID:PMC5496788

[172] Mitchell TC,Smith DC,Wasser JS.Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase i results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037)..J Clin Oncol2018; PMCID:PMC6225502

[173] Long GV,Hamid O,Caglevic C.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 Oncol2019;20:1083-97

[174] Kerbel RS.Tumor angiogenesis..N Engl J Med2008;358:2039-49 PMCID:PMC4542009

[175] Motz GT,Wang LP,Lastra RR.Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors..Nat Med2014;20:607-15 PMCID:PMC4060245

[176] Chen PL,Reuben A,Spencer CN.Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade..Cancer Discov2016;6:827-37 PMCID:PMC5082984

[177] Voron T,Marcheteau E,Nizard M.VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors..J Exp Med2015;212:139-48 PMCID:PMC4322048

[178] Ohm JE,Sempowski GD,Parman KS.VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression..Blood2003;101:4878-86

[179] Terme M,Marcheteau E,Benhamouda N.VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer..Cancer Res2013;73:539-49

[180] Yasuda S,Yamato I,Wakatsuki K.Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo..Clin Exp Immunol2013;172:500-6 PMCID:PMC3646450

[181] Wallin JJ,Funke R,Korski K.Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma..Nat Commun2016;7:12624 PMCID:PMC5013615

[182] Bergerot P,Wang E.Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: rationale and clinical evidence..Mol Cancer Ther2019;18:2185-93

[183] Rini BI,Stus V,Hawkins R.Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma..N Engl J Med2019;380:1116-27

[184] Motzer RJ,Haanen J,Albiges L.Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma..N Engl J Med2019;380:1103-15 PMCID:PMC6716603

[185] Hsu C-H,Lee KH,Stein S.LBA7Randomised efficacy and safety results for atezolizumab (Atezo) + bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC)..Ann Oncol2019;30:

[186] Lane ER,Suskind DL.The microbiota in inflammatory bowel disease: current and therapeutic insights..J Inflamm Res2017;10:63-73 PMCID:PMC5473501

[187] Zitvogel L,Roberti MP,Kroemer G.Anticancer effects of the microbiome and its products..Nat Rev Microbiol2017;15:465-78

[188] Zitvogel L,Routy B.Microbiome and anticancer immunosurveillance..Cell2016;165:276-87

[189] Fessler J,Gajewski TF.Exploring the emerging role of the microbiome in cancer immunotherapy..J Immunother Cancer2019;7:108 PMCID:PMC6471869

[190] Gopalakrishnan V,Nezi L,Andrews MC.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients..Science2018;359:97-103 PMCID:PMC5827966

[191] Matson V,Bao R,Zha Y.The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients..Science2018;359:104-8 PMCID:PMC6707353

[192] Routy B,Derosa L,Alou MT.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors..Science2018;359:91-7

[193] Vetizou M,Daillere R,Waldschmitt N.Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota..Science2015;350:1079-84 PMCID:PMC4721659

[194] Derosa L,Spaziano M,Fidelle M.Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer..Ann Oncol2018;29:1437-44 PMCID:PMC6354674

[195] Pinato DJ,Ottaviani D,Patel A.Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer..JAMA Oncol2019;5:1774-8 PMCID:PMC6743060

[196] Sivan A,Hubert N,Aquino-Michaels K.Commensal bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy..Science2015;350:1084-9 PMCID:PMC4873287

[197] Baruch EN,Ortenberg R,Katz LH.Abstract CT042: fecal microbiota transplantation (FMT) and re-induction of anti-PD-1 therapy in refractory metastatic melanoma patients - preliminary results from a phase I clinical trial (NCT03353402)..Cancer Res2019;79:CT042-CT

[198] Butterfield LH,Fox BA,Khleif SN.SITC 2018 workshop report: immuno-oncology biomarkers: state of the art..J Immunother Cancer2018;6:138 PMCID:PMC6278162

[199] Balli D,Stanger BZ.Immune cytolytic activity stratifies molecular subsets of human pancreatic cancer..Clin Cancer Res2017;23:3129-38

[200] Blando J,Higa MG,Vence L.Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer..Proc Natl Acad Sci U S A2019;116:1692-7 PMCID:PMC6358697

[201] Lee JJ,Patel MR,Hamilton EP.Phase 1 trial of CA-170, a novel oral small molecule dual inhibitor of immune checkpoints PD-1 and VISTA, in patients (pts) with advanced solid tumor or lymphomas..J Clin Oncol2017;35:TPS3099

[202] Tolcher AW,Hu-Lieskovan S,Patnaik A.Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with pembrolizumab (MK-3475) in patients with advanced solid tumors..Clin Cancer Res2017;23:5349-57

[203] Soldevilla MM,Meraviglia-Crivelli D,Ruiz M.ICOS costimulation at the tumor site in combination with CTLA-4 blockade therapy elicits strong tumor immunity..Mol Ther2019;27:1878-91 PMCID:PMC6838990

[204] Zappasodi R,Li Y,Abu-Akeel M.Rational design of anti-GITR-based combination immunotherapy..Nat Med2019;25:759-66

[205] Suzuki E,Jassar AS,Albelda SM.Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity..Clin Cancer Res2005;11:6713-21

[206] Germano G,Rospo G,Magrì A.Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth..Nature2017;552:116-20

[207] Wakita D,Harada S,Yamamoto K.Cisplatin augments antitumor T-cell responses leading to a potent therapeutic effect in combination with PD-L1 blockade..Anticancer Res2019;39:1749-60

[208] Zhu L.Progress in research on paclitaxel and tumor immunotherapy..Cell Mol Biol Lett2019;24:40 PMCID:PMC6567594

[209] Ganesh S,Craig KP,Wang W.RNAi-mediated β-catenin inhibition promotes T cell infiltration and antitumor activity in combination with immune checkpoint blockade..Mol Ther2018;26:2567-79 PMCID:PMC6225018

[210] Kawazoe A,Komatsu Y,Shinozaki E.Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503..J Clin Oncol2018;36:760

[211] Luo N,Gonzalez-Ericsson PI,Dean PT.Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2..Oncoimmunology2018;7:e1438106 PMCID:PMC5975601

[212] Schaer DA,Dempsey JA,Forest A.The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade..Cell Rep2018;22:2978-94

[213] Jiang P,Pan D,Sahu A.Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response..Nat Med2018;24:1550-8 PMCID:PMC6487502

[214] Beavis PA,Henderson MA,Allard B.Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses..Cancer Immunol Res2015;3:506-17

[215] Chen L,Yang Y,Rodriguez BL.CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade..Cancer Discov2018;8:1156-75 PMCID:PMC6205194

[216] Maj T,Crespo J,Wang W.Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor..Nat Immunol2017;18:1332-41 PMCID:PMC5770150

[217] Perrot I,Giraudon-Paoli M,Docquier A.Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies..Cell Rep2019;27:2411-25.e9

[218] Iannone R,Maiolino P,Morello S.Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model..Am J Cancer Res2014;4:172-81 PMCID:PMC3960454

[219] Leone RD,Oh MH,Wen J.Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models..Cancer Immunol Immunother2018;67:1271-84

[220] Doi T,Ishii H,Tsushima T.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 Res2019;25:6614-22

[221] Buchbinder EI,Daniels GA,Patel SP.Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition..J Immunother Cancer2019;7:49 PMCID:PMC6380045

[222] Puca E,Stringhini M,Pellegrini G.The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8(+) T cell activity and synergizes with immune checkpoint inhibitors..Int J Cancer2020;146:2518-30

[223] Berraondo P,Ponz-Sarvise M.Revisiting interleukin-12 as a cancer immunotherapy agent..Clin Cancer Res2018;24:2716-8

[224] Zhao M,Xie Y,Cagliero C.Development of a recombinant human IL-15·sIL-15Rα/Fc superagonist with improved half-life and its antitumor activity alone or in combination with PD-1 blockade in mouse model..Biomed Pharmacother2019;112:108677

[225] Jung H,Ebsworth K,Schall T.Combination therapy of chemokine receptor inhibition plus PDL-1 blockade potentiates anti-tumor effects in a murine model of breast cancer..J Immunother Cancer2015;3:P227 PMCID:PMC4649449

[226] Flores-Toro JA,Gopinath A,Campbell JJ.CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas..Proc Natl Acad Sci U S A2020;117:1129-38 PMCID:PMC6969504

[227] Jung H,Janson C,Charo I.Abstract A107: Inhibition of CCR2 potentiates the checkpoint inhibitor immunotherapy in pancreatic cancer..Cancer Immunol Res2016;4:A107

[228] Dominguez C,David JM.Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer..JCI insight2017;2:e94296 PMCID:PMC5752275

[229] Greene S,Mydlarz WK,Schmitt NC.Inhibition of MDSC trafficking with SX-682, a CXCR1/2 inhibitor, enhances NK-Cell immunotherapy in head and neck cancer models..Clin Cancer Res2020;26:1420-31 PMCID:PMC7073293

[230] Steele CW,Leach JDG,Upstill-Goddard R.CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma..Cancer Cell2016;29:832-45 PMCID:PMC4912354

[231] Mullinax JE,Prabhakaran S,Khushalani N.Combination of ipilimumab and adoptive cell therapy with tumor-infiltrating lymphocytes for patients with metastatic melanoma..Front Oncol2018;8:44 PMCID:PMC5840208

[232] Zhang R,Jiang YY,Wang J.Effect and changes in PD-1 expression of CD19 CAR-T cells from T cells highly expressing PD-1 combined with reduced-dose PD-1 inhibitor..Oncol Rep2019;41:3455-63

[233] Peng M,Wang Y,Zhang Y.Neoantigen vaccine: an emerging tumor immunotherapy..Molecular Cancer2019;18: PMCID:PMC6708248

[234] Wang T,Luo Q,He B.Probiotics lactobacillus reuteri abrogates immune checkpoint blockade-associated colitis by inhibiting group 3 innate lymphoid cells..Front Immunol2019;10:1235 PMCID:PMC6558076

[235] Deng L,Burnette B,Darga T.Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice..J Clin Invest2014;124:687-95 PMCID:PMC3904601

[236] Twyman-Saint Victor C,Maity A,Pauken KE.Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer..Nature2015;520:373-7 PMCID:PMC4401634

[237] Demaria S,Formenti SC.Role of local radiation therapy in cancer immunotherapy..JAMA Oncol2015;1:1325-32

[238] Lemdani K,Boudy V,Oujagir E.Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma..Oncoimmunology2019;8:1550342 PMCID:PMC6350685

[239] Aarts BM,Rice SL,Baetens T.Cryoablation and immunotherapy: an overview of evidence on its synergy..Insights into Imaging2019;10: PMCID:PMC6527672

[240] Ray A,Meek SM,Grossmann KF.A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma..Oncotarget2016;7:64390-9 PMCID:PMC5325451

[241] Weide B,Pflugfelder A,Radny P.High response rate after intratumoral treatment with interleukin-2: results from a phase 2 study in 51 patients with metastasized melanoma..Cancer2010;116:4139-46

[242] Langan EA,Graetz V,Zillikens D.Intralesional interleukin-2: a novel option to maximize response to systemic immune checkpoint therapy in loco-regional metastatic melanoma..Dermatol Ther2019;32:e12901

[243] Rafei-Shamsabadi D,von Bubnoff D.Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone..Cancer Immunol Immunother2019;68:1417-28

[244] Chowdhury S,Coker C,Arpaia N.Programmable bacteria induce durable tumor regression and systemic antitumor immunity..Nat Med2019;25:1057-63 PMCID:PMC6688650

[245] Marabelle A,De Baere T.Intratumoral immunotherapy: using the tumor as the remedy..Ann Oncol2017;28:xii33-43

[246] Wang Y,Yang X,Liu Y.Bacillus Calmette-Guérin and anti-PD-L1 combination therapy boosts immune response against bladder cancer..Onco Targets Ther2018;11:2891-9 PMCID:PMC5962256