Advertisement

Seminars in Immunopathology

, Volume 41, Issue 1, pp 31–40 | Cite as

Acquired resistance to cancer immunotherapy

  • Arianna Draghi
  • Christopher Aled Chamberlain
  • Andrew Furness
  • Marco DoniaEmail author
Review

Abstract

In recent times, advances in cancer immunotherapy have yielded impressive, durable clinical responses in patients with varied subtypes of cancer. However, a significant proportion of patients who initially demonstrate encouraging tumor regression develop resistance and progress over time. The identification of novel therapeutic approaches to overcome resistance may result in significantly improved clinical outcomes and remains an area of high scientific priority. This review aims to summarize the current knowledge regarding the role of both tumor-intrinsic and tumor-extrinsic factors in the development of resistance to cancer immunotherapy and to discuss current and possible future therapeutic strategies targeting these mechanisms.

Keywords

Acquired resistance Cancer immunotherapy Checkpoint inhibitors Immune evasion Immune escape 

Notes

Compliance with ethical standards

Conflict of interest

Marco Donia has received honoraria for lectures from Bristol-Myers Squibb, Merck, Astra Zeneca, and Genzyme, as well as financial support for attending symposia from Bristol-Myers Squibb, Merck, Novartis, Pfizer, and Roche. The other authors declare that they have no conflict of interest.

References

  1. 1.
    Sharma P, Allison JP (2015) The future of immune checkpoint therapy. Science 348(6230):56–61.  https://doi.org/10.1126/science.aaa8172 Google Scholar
  2. 2.
    Restifo NP, Smyth MJ, Snyder A (2016) Acquired resistance to immunotherapy and future challenges. Nat Rev Cancer 16(2):121–126.  https://doi.org/10.1038/nrc.2016.2 Google Scholar
  3. 3.
    Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12(4):269–281.  https://doi.org/10.1038/nri3191 Google Scholar
  4. 4.
    Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C (2016) Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 315(15):1600–1609.  https://doi.org/10.1001/jama.2016.4059 Google Scholar
  5. 5.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34.  https://doi.org/10.1056/NEJMoa1504030 Google Scholar
  6. 6.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A, investigators K (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532.  https://doi.org/10.1056/NEJMoa1503093 Google Scholar
  7. 7.
    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372(21):2006–2017.  https://doi.org/10.1056/NEJMoa1414428 Google Scholar
  8. 8.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723.  https://doi.org/10.1056/NEJMoa1003466 Google Scholar
  9. 9.
    Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR, Investigators K (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833.  https://doi.org/10.1056/NEJMoa1606774 Google Scholar
  10. 10.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639.  https://doi.org/10.1056/NEJMoa1507643 Google Scholar
  11. 11.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135.  https://doi.org/10.1056/NEJMoa1504627 Google Scholar
  12. 12.
    Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JA, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18(3):312–322.  https://doi.org/10.1016/S1470-2045(17)30065-7 Google Scholar
  13. 13.
    Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387(10031):1909–1920.  https://doi.org/10.1016/S0140-6736(16)00561-4 Google Scholar
  14. 14.
    Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, Lee JL, Ong M, Sridhar SS, Vogelzang NJ, Fishman MN, Zhang J, Srinivas S, Parikh J, Antal J, Jin X, Gupta AK, Ben Y, Hahn NM (2017) Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 3(9):e172411.  https://doi.org/10.1001/jamaoncol.2017.2411 Google Scholar
  15. 15.
    Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, Saba NF, Weiss J, Wirth L, Sukari A, Kang H, Gibson MK, Massarelli E, Powell S, Meister A, Shu X, Cheng JD, Haddad R (2017) Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol 35(14):1542–1549.  https://doi.org/10.1200/JCO.2016.70.1524 Google Scholar
  16. 16.
    Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, Cheng JD, Chow LQ (2016) Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 17(7):956–965.  https://doi.org/10.1016/S1470-2045(16)30066-3 Google Scholar
  17. 17.
    Harrington KJ, Ferris RL, Blumenschein G Jr, Colevas AD, Fayette J, Licitra L, Kasper S, Even C, Vokes EE, Worden F, Saba NF, Kiyota N, Haddad R, Tahara M, Grunwald V, Shaw JW, Monga M, Lynch M, Taylor F, DeRosa M, Morrissey L, Cocks K, Gillison ML, Guigay J (2017) Nivolumab versus standard, single-agent therapy of investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol 18(8):1104–1115.  https://doi.org/10.1016/S1470-2045(17)30421-7 Google Scholar
  18. 18.
    Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, CheckMate I (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813.  https://doi.org/10.1056/NEJMoa1510665 Google Scholar
  19. 19.
    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319.  https://doi.org/10.1056/NEJMoa1411087 Google Scholar
  20. 20.
    Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J, Snyder ES, Ricart AD, Balakumaran A, Rose S, Moskowitz CH (2016) Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 34(31):3733–3739.  https://doi.org/10.1200/JCO.2016.67.3467 Google Scholar
  21. 21.
    Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, Radford J, Ribrag V, Molin D, Vassilakopoulos TP, Tomita A, von Tresckow B, Shipp MA, Zhang Y, Ricart AD, Balakumaran A, Moskowitz CH, Keynote (2017) Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 35(19):2125–2132.  https://doi.org/10.1200/JCO.2016.72.1316 Google Scholar
  22. 22.
    Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D’Angelo SP, Shih KC, Lebbe C, Linette GP, Milella M, Brownell I, Lewis KD, Lorch JH, Chin K, Mahnke L, von Heydebreck A, Cuillerot JM, Nghiem P (2016) Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17(10):1374–1385.  https://doi.org/10.1016/S1470-2045(16)30364-3 Google Scholar
  23. 23.
    Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, Berry S, Chartash EK, Daud A, Fling SP, Friedlander PA, Kluger HM, Kohrt HE, Lundgren L, Margolin K, Mitchell A, Olencki T, Pardoll DM, Reddy SA, Shantha EM, Sharfman WH, Sharon E, Shemanski LR, Shinohara MM, Sunshine JC, Taube JM, Thompson JA, Townson SM, Yearley JH, Topalian SL, Cheever MA (2016) PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 374(26):2542–2552.  https://doi.org/10.1056/NEJMoa1603702 Google Scholar
  24. 24.
    Alley EW, Lopez J, Santoro A, Morosky A, Saraf S, Piperdi B, van Brummelen E (2017) Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol 18(5):623–630.  https://doi.org/10.1016/S1470-2045(17)30169-9 Google Scholar
  25. 25.
    Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348(6230):69–74.  https://doi.org/10.1126/science.aaa4971 Google Scholar
  26. 26.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264.  https://doi.org/10.1038/nrc3239 Google Scholar
  27. 27.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704.  https://doi.org/10.1146/annurev.immunol.26.021607.090331 Google Scholar
  28. 28.
    Quezada SA, Peggs KS (2013) Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer 108(8):1560–1565.  https://doi.org/10.1038/bjc.2013.117 Google Scholar
  29. 29.
    Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182(2):459–465Google Scholar
  30. 30.
    Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526.  https://doi.org/10.1056/NEJMoa1104621 Google Scholar
  31. 31.
    Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33(17):1889–1894.  https://doi.org/10.1200/JCO.2014.56.2736 Google Scholar
  32. 32.
    Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C (2017) Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390(10105):1853–1862.  https://doi.org/10.1016/S0140-6736(17)31601-X Google Scholar
  33. 33.
    FDA (2018) Novel drug approvals for 2016. FDA website https://wwwfdagov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm483775htm Accessed 02 May 2018
  34. 34.
    FDA (2018) Novel drug approvals for 2017. FDA Website https://wwwfdagov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm537040htm Accessed 02 May 2018
  35. 35.
    Geukes Foppen MH, Donia M, Svane IM, Haanen JB (2015) Tumor-infiltrating lymphocytes for the treatment of metastatic cancer. Mol Oncol 9(10):1918–1935.  https://doi.org/10.1016/j.molonc.2015.10.018 Google Scholar
  36. 36.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507–1517.  https://doi.org/10.1056/NEJMoa1407222 Google Scholar
  37. 37.
    Han S, Latchoumanin O, Wu G, Zhou G, Hebbard L, George J, Qiao L (2017) Recent clinical trials utilizing chimeric antigen receptor T cells therapies against solid tumors. Cancer Lett 390:188–200.  https://doi.org/10.1016/j.canlet.2016.12.037 Google Scholar
  38. 38.
    Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29(7):917–924.  https://doi.org/10.1200/JCO.2010.32.2537 Google Scholar
  39. 39.
    Karpanen T, Olweus J (2015) T-cell receptor gene therapy—ready to go viral? Mol Oncol 9(10):2019–2042.  https://doi.org/10.1016/j.molonc.2015.10.006 Google Scholar
  40. 40.
    Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Lower M, Bukur V, Tadmor AD, Luxemburger U, Schrors B, Omokoko T, Vormehr M, Albrecht C, Paruzynski A, Kuhn AN, Buck J, Heesch S, Schreeb KH, Muller F, Ortseifer I, Vogler I, Godehardt E, Attig S, Rae R, Breitkreuz A, Tolliver C, Suchan M, Martic G, Hohberger A, Sorn P, Diekmann J, Ciesla J, Waksmann O, Bruck AK, Witt M, Zillgen M, Rothermel A, Kasemann B, Langer D, Bolte S, Diken M, Kreiter S, Nemecek R, Gebhardt C, Grabbe S, Holler C, Utikal J, Huber C, Loquai C, Tureci O (2017) Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547(7662):222–226.  https://doi.org/10.1038/nature23003 Google Scholar
  41. 41.
    Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L, Chen C, Olive O, Carter TA, Li S, Lieb DJ, Eisenhaure T, Gjini E, Stevens J, Lane WJ, Javeri I, Nellaiappan K, Salazar AM, Daley H, Seaman M, Buchbinder EI, Yoon CH, Harden M, Lennon N, Gabriel S, Rodig SJ, Barouch DH, Aster JC, Getz G, Wucherpfennig K, Neuberg D, Ritz J, Lander ES, Fritsch EF, Hacohen N, Wu CJ (2018) Corrigendum: an immunogenic personal neoantigen vaccine for patients with melanoma. Nature 555(7696):402.  https://doi.org/10.1038/nature25145 Google Scholar
  42. 42.
    Burke EE, Zager JS (2018) Pharmacokinetic drug evaluation of talimogene laherparepvec for the treatment of advanced melanoma. Expert Opin Drug Metab Toxicol 14(4):469–473.  https://doi.org/10.1080/17425255.2018.1455825 Google Scholar
  43. 43.
    Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ, Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Chen L, Gorski KS, Anderson AA, Diede SJ, Lassman ME, Gansert J, Hodi FS, Long GV (2017) Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170(6):1109–1119 e1110.  https://doi.org/10.1016/j.cell.2017.08.027 Google Scholar
  44. 44.
    Ribas A (2015) Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov 5(9):915–919.  https://doi.org/10.1158/2159-8290.CD-15-0563 Google Scholar
  45. 45.
    Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4):707–723.  https://doi.org/10.1016/j.cell.2017.01.017 Google Scholar
  46. 46.
    Pitt JM, Vetizou M, Daillere R, Roberti MP, Yamazaki T, Routy B, Lepage P, Boneca IG, Chamaillard M, Kroemer G, Zitvogel L (2016) Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity 44(6):1255–1269.  https://doi.org/10.1016/j.immuni.2016.06.001 Google Scholar
  47. 47.
    Syn NL, Teng MWL, Mok TSK, Soo RA (2017) De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol 18(12):e731–e741.  https://doi.org/10.1016/S1470-2045(17)30607-1 Google Scholar
  48. 48.
    Jenkins RW, Barbie DA, Flaherty KT (2018) Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer 118(1):9–16.  https://doi.org/10.1038/bjc.2017.434 Google Scholar
  49. 49.
    O’Donnell JS, Long GV, Scolyer RA, Teng MW, Smyth MJ (2017) Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat Rev 52:71–81.  https://doi.org/10.1016/j.ctrv.2016.11.007 Google Scholar
  50. 50.
    Ward JP, Gubin MM, Schreiber RD (2016) The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer. Adv Immunol 130:25–74.  https://doi.org/10.1016/bs.ai.2016.01.001 Google Scholar
  51. 51.
    Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, Holt RA (2014) Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res 24(5):743–750.  https://doi.org/10.1101/gr.165985.113 Google Scholar
  52. 52.
    Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N (2015) Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160(1–2):48–61.  https://doi.org/10.1016/j.cell.2014.12.033 Google Scholar
  53. 53.
    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230):124–128.  https://doi.org/10.1126/science.aaa1348 Google Scholar
  54. 54.
    Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23):2189–2199.  https://doi.org/10.1056/NEJMoa1406498 Google Scholar
  55. 55.
    Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Foppen MHG, Goldinger SM, Utikal J, Hassel JC, Weide B, Kaehler KC, Loquai C, Mohr P, Gutzmer R, Dummer R, Gabriel S, Wu CJ, Schadendorf D, Garraway LA (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257):207–211.  https://doi.org/10.1126/science.aad0095 Google Scholar
  56. 56.
    Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, Hodi FS, Martin-Algarra S, Mandal R, Sharfman WH, Bhatia S, Hwu WJ, Gajewski TF, Slingluff CL Jr, Chowell D, Kendall SM, Chang H, Shah R, Kuo F, Morris LGT, Sidhom JW, Schneck JP, Horak CE, Weinhold N, Chan TA (2017) Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171(4):934–949 e915.  https://doi.org/10.1016/j.cell.2017.09.028 Google Scholar
  57. 57.
    Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R, White J, Zhang T, Adleff V, Phallen J, Wali N, Hruban C, Guthrie VB, Rodgers K, Naidoo J, Kang H, Sharfman W, Georgiades C, Verde F, Illei P, Li QK, Gabrielson E, Brock MV, Zahnow CA, Baylin SB, Scharpf RB, Brahmer JR, Karchin R, Pardoll DM, Velculescu VE (2017) Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov 7(3):264–276.  https://doi.org/10.1158/2159-8290.CD-16-0828 Google Scholar
  58. 58.
    Verdegaal EM, de Miranda NF, Visser M, Harryvan T, van Buuren MM, Andersen RS, Hadrup SR, van der Minne CE, Schotte R, Spits H, Haanen JB, Kapiteijn EH, Schumacher TN, van der Burg SH (2016) Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature 536(7614):91–95.  https://doi.org/10.1038/nature18945 Google Scholar
  59. 59.
    Kaluza KM, Thompson JM, Kottke TJ, Flynn Gilmer HC, Knutson DL, Vile RG (2012) Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants. Int J Cancer 131(4):844–854.  https://doi.org/10.1002/ijc.26447 Google Scholar
  60. 60.
    Landsberg J, Kohlmeyer J, Renn M, Bald T, Rogava M, Cron M, Fatho M, Lennerz V, Wolfel T, Holzel M, Tuting T (2012) Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490(7420):412–416.  https://doi.org/10.1038/nature11538 Google Scholar
  61. 61.
    Knutson KL, Lu H, Stone B, Reiman JM, Behrens MD, Prosperi CM, Gad EA, Smorlesi A, Disis ML (2006) Immunoediting of cancers may lead to epithelial to mesenchymal transition. J Immunol 177(3):1526–1533Google Scholar
  62. 62.
    Santisteban M, Reiman JM, Asiedu MK, Behrens MD, Nassar A, Kalli KR, Haluska P, Ingle JN, Hartmann LC, Manjili MH, Radisky DC, Ferrone S, Knutson KL (2009) Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res 69(7):2887–2895.  https://doi.org/10.1158/0008-5472.CAN-08-3343 Google Scholar
  63. 63.
    Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, Pasetto A, Zheng Z, Ray S, Groh EM, Kriley IR, Rosenberg SA (2016) T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med 375(23):2255–2262.  https://doi.org/10.1056/NEJMoa1609279 Google Scholar
  64. 64.
    Haanen J (2017) Cancer immunotherapy: escape of response. [Article released in occasion of ESMO Immuno-Oncology Congress 2017]Google Scholar
  65. 65.
    O’Donnell JS, Smyth MJ, Teng MW (2016) Acquired resistance to anti-PD1 therapy: checkmate to checkpoint blockade? Genome Med 8(1):111.  https://doi.org/10.1186/s13073-016-0365-1 Google Scholar
  66. 66.
    Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, Saco J, Homet Moreno B, Mezzadra R, Chmielowski B, Ruchalski K, Shintaku IP, Sanchez PJ, Puig-Saus C, Cherry G, Seja E, Kong X, Pang J, Berent-Maoz B, Comin-Anduix B, Graeber TG, Tumeh PC, Schumacher TN, Lo RS, Ribas A (2016) Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 375(9):819–829.  https://doi.org/10.1056/NEJMoa1604958 Google Scholar
  67. 67.
    Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP, Bjorgaard SL, Hammond MR, Vitzthum H, Blackmon SM, Frederick DT, Hazar-Rethinam M, Nadres BA, Van Seventer EE, Shukla SA, Yizhak K, Ray JP, Rosebrock D, Livitz D, Adalsteinsson V, Getz G, Duncan LM, Li B, Corcoran RB, Lawrence DP, Stemmer-Rachamimov A, Boland GM, Landau DA, Flaherty KT, Sullivan RJ, Hacohen N (2017) Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun 8(1):1136.  https://doi.org/10.1038/s41467-017-01062-w Google Scholar
  68. 68.
    Gettinger S, Choi J, Hastings K, Truini A, Datar I, Sowell R, Wurtz A, Dong W, Cai G, Melnick MA, Du VY, Schlessinger J, Goldberg SB, Chiang A, Sanmamed MF, Melero I, Agorreta J, Montuenga LM, Lifton R, Ferrone S, Kavathas P, Rimm DL, Kaech SM, Schalper K, Herbst RS, Politi K (2017) Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov 7(12):1420–1435.  https://doi.org/10.1158/2159-8290.CD-17-0593 Google Scholar
  69. 69.
    Chang CC, Pirozzi G, Wen SH, Chung IH, Chiu BL, Errico S, Luongo M, Lombardi ML, Ferrone S (2015) Multiple structural and epigenetic defects in the human leukocyte antigen class I antigen presentation pathway in a recurrent metastatic melanoma following immunotherapy. J Biol Chem 290(44):26562–26575.  https://doi.org/10.1074/jbc.M115.676130 Google Scholar
  70. 70.
    Donia M, Harbst K, van Buuren M, Kvistborg P, Lindberg MF, Andersen R, Idorn M, Munir Ahmad S, Ellebaek E, Mueller A, Fagone P, Nicoletti F, Libra M, Lauss M, Hadrup SR, Schmidt H, Andersen MH, Thor Straten P, Nilsson JA, Schumacher TN, Seliger B, Jonsson G, Svane IM (2017) Acquired immune resistance follows complete tumor regression without loss of target antigens or IFNgamma signaling. Cancer Res 77(17):4562–4566.  https://doi.org/10.1158/0008-5472.CAN-16-3172 Google Scholar
  71. 71.
    Sucker A, Zhao F, Pieper N, Heeke C, Maltaner R, Stadtler N, Real B, Bielefeld N, Howe S, Weide B, Gutzmer R, Utikal J, Loquai C, Gogas H, Klein-Hitpass L, Zeschnigk M, Westendorf AM, Trilling M, Horn S, Schilling B, Schadendorf D, Griewank KG, Paschen A (2017) Acquired IFNgamma resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions. Nat Commun 8:15440.  https://doi.org/10.1038/ncomms15440 Google Scholar
  72. 72.
    Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, Grasso CS, Hugo W, Sandoval S, Torrejon DY, Palaskas N, Rodriguez GA, Parisi G, Azhdam A, Chmielowski B, Cherry G, Seja E, Berent-Maoz B, Shintaku IP, Le DT, Pardoll DM, Diaz LA Jr, Tumeh PC, Graeber TG, Lo RS, Comin-Anduix B, Ribas A (2017) Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 7(2):188–201.  https://doi.org/10.1158/2159-8290.CD-16-1223 Google Scholar
  73. 73.
    Bach EA, Aguet M, Schreiber RD (1997) The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol 15:563–591.  https://doi.org/10.1146/annurev.immunol.15.1.563 Google Scholar
  74. 74.
    Fish EN, Platanias LC (2014) Interferon receptor signaling in malignancy: a network of cellular pathways defining biological outcomes. Mol Cancer Res 12(12):1691–1703.  https://doi.org/10.1158/1541-7786.MCR-14-0450 Google Scholar
  75. 75.
    Dunn GP, Sheehan KC, Old LJ, Schreiber RD (2005) IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. Cancer Res 65(8):3447–3453.  https://doi.org/10.1158/0008-5472.CAN-04-4316 Google Scholar
  76. 76.
    Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD (1998) Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A 95(13):7556–7561Google Scholar
  77. 77.
    Gao J, Shi LZ, Zhao H, Chen J, Xiong L, He Q, Chen T, Roszik J, Bernatchez C, Woodman SE, Chen PL, Hwu P, Allison JP, Futreal A, Wargo JA, Sharma P (2016) Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167(2):397–404 e399.  https://doi.org/10.1016/j.cell.2016.08.069 Google Scholar
  78. 78.
    Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461.  https://doi.org/10.1016/j.ccell.2015.03.001 Google Scholar
  79. 79.
    Benci JL, Xu B, Qiu Y, Wu TJ, Dada H, Twyman-Saint Victor C, Cucolo L, Lee DSM, Pauken KE, Huang AC, Gangadhar TC, Amaravadi RK, Schuchter LM, Feldman MD, Ishwaran H, Vonderheide RH, Maity A, Wherry EJ, Minn AJ (2016) Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167(6):1540–1554 e1512.  https://doi.org/10.1016/j.cell.2016.11.022 Google Scholar
  80. 80.
    Thommen D, Uhlenbrock F, Herzig P, Prince SS, Moersig W, Lardinois D, Zippelius A (2016) 66P Highly exhausted PD-1hi T cell subsets in human NSCLC are co-defined by the predominant expression of distinct inhibitory receptors and correlate with clinical outcome. J Thorac Oncol 11(4 Suppl):S83.  https://doi.org/10.1016/S1556-0864(16)30179-4 Google Scholar
  81. 81.
    Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, Zhao H, Chen J, Chen H, Efstathiou E, Troncoso P, Allison JP, Logothetis CJ, Wistuba II, Sepulveda MA, Sun J, Wargo J, Blando J, Sharma P (2017) VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 23(5):551–555.  https://doi.org/10.1038/nm.4308 Google Scholar
  82. 82.
    Huang RY, Francois A, McGray AR, Miliotto A, Odunsi K (2017) Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology 6(1):e1249561.  https://doi.org/10.1080/2162402X.2016.1249561 Google Scholar
  83. 83.
    Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H, Jones RE, Kulkarni MM, Kuraguchi M, Palakurthi S, Fecci PE, Johnson BE, Janne PA, Engelman JA, Gangadharan SP, Costa DB, Freeman GJ, Bueno R, Hodi FS, Dranoff G, Wong KK, Hammerman PS (2016) Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 7:10501.  https://doi.org/10.1038/ncomms10501 Google Scholar
  84. 84.
    Shayan G, Srivastava R, Li J, Schmitt N, Kane LP, Ferris RL (2017) Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer. Oncoimmunology 6(1):e1261779.  https://doi.org/10.1080/2162402X.2016.1261779 Google Scholar
  85. 85.
    Balko JM JD, Wang DY, Ericsson-Gonzalez P, Nixon M, Salgado R, Sanchez V, Schreeder D, Kim JY, Bordeaux J, Sanders M, Davis RS (2018) MHC-II expression to drive a unique pattern of adaptive resistance to antitumor immunity through receptor checkpoint engagement. J Clin Oncol 36, 2018 (suppl 5S; abstr 180) Poster from ASCO-SITC Clinical Immuno-Oncology Symposum 2018Google Scholar
  86. 86.
    Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, Bettini ML, Gravano DM, Vogel P, Liu CL, Tangsombatvisit S, Grosso JF, Netto G, Smeltzer MP, Chaux A, Utz PJ, Workman CJ, Pardoll DM, Korman AJ, Drake CG, Vignali DA (2012) Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 72(4):917–927.  https://doi.org/10.1158/0008-5472.CAN-11-1620 Google Scholar
  87. 87.
    Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC (2010) Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 207(10):2187–2194.  https://doi.org/10.1084/jem.20100643 Google Scholar
  88. 88.
    Ascierto PA, Melero I, Bhatia S, Bono P, Sanborn RE, Lipson EJ, Callahan MK, Gajewski T, Gomez-Roca CA, Hodi FS, Curigliano G, Nyakas M, Preusser M, Koguchi Y, Maurer M, Clynes R, Mitra P, Suryawanshi S, Muñoz-Couselo E (2017) Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy. J Clin Oncol 35(15_suppl):9520–9520.  https://doi.org/10.1200/JCO.2017.35.15_suppl.9520 Google Scholar
  89. 89.
    Bertrand F, Montfort A, Marcheteau E, Imbert C, Gilhodes J, Filleron T, Rochaix P, Andrieu-Abadie N, Levade T, Meyer N, Colacios C, Segui B (2017) TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat Commun 8(1):2256.  https://doi.org/10.1038/s41467-017-02358-7 Google Scholar
  90. 90.
    Luke JJ, Bao R, Spranger S, Sweis RF, Gajewski T (2016) Correlation of WNT/β-catenin pathway activation with immune exclusion across most human cancers. J Clin Oncol 34(15_suppl):3004–3004.  https://doi.org/10.1200/JCO.2016.34.15_suppl.3004 Google Scholar
  91. 91.
    Gallagher SJ, Shklovskaya E, Hersey P (2017) Epigenetic modulation in cancer immunotherapy. Curr Opin Pharmacol 35:48–56.  https://doi.org/10.1016/j.coph.2017.05.006 Google Scholar
  92. 92.
    Nagarsheth N, Peng D, Kryczek I, Wu K, Li W, Zhao E, Zhao L, Wei S, Frankel T, Vatan L, Szeliga W, Dou Y, Owens S, Marquez V, Tao K, Huang E, Wang G, Zou W (2016) PRC2 epigenetically silences Th1-type chemokines to suppress effector T-cell trafficking in colon cancer. Cancer Res 76(2):275–282.  https://doi.org/10.1158/0008-5472.CAN-15-1938 Google Scholar
  93. 93.
    Shitara K, Nishikawa H (2018) Regulatory T cells: a potential target in cancer immunotherapy. Ann N Y Acad Sci 1417:104–115.  https://doi.org/10.1111/nyas.13625 Google Scholar
  94. 94.
    Commeren DL, Van Soest PL, Karimi K, Lowenberg B, Cornelissen JJ, Braakman E (2003) Paradoxical effects of interleukin-10 on the maturation of murine myeloid dendritic cells. Immunology 110(2):188–196Google Scholar
  95. 95.
    Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M, Korman AJ (2013) Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res 1(1):32–42.  https://doi.org/10.1158/2326-6066.CIR-13-0013 Google Scholar
  96. 96.
    Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, Peggs KS, Ravetch JV, Allison JP, Quezada SA (2013) Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 210(9):1695–1710.  https://doi.org/10.1084/jem.20130579 Google Scholar
  97. 97.
    Bulliard Y, Jolicoeur R, Windman M, Rue SM, Ettenberg S, Knee DA, Wilson NS, Dranoff G, Brogdon JL (2013) Activating Fc gamma receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med 210(9):1685–1693.  https://doi.org/10.1084/jem.20130573 Google Scholar
  98. 98.
    Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, Michielin O, Weide B, Romero P, Speiser DE (2015) Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A 112(19):6140–6145.  https://doi.org/10.1073/pnas.1417320112 Google Scholar
  99. 99.
    Tarhini AA, Edington H, Butterfield LH, Lin Y, Shuai Y, Tawbi H, Sander C, Yin Y, Holtzman M, Johnson J, Rao UN, Kirkwood JM (2014) Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One 9(2):e87705.  https://doi.org/10.1371/journal.pone.0087705 Google Scholar
  100. 100.
    Jie HB, Schuler PJ, Lee SC, Srivastava RM, Argiris A, Ferrone S, Whiteside TL, Ferris RL (2015) CTLA-4(+) regulatory T cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res 75(11):2200–2210.  https://doi.org/10.1158/0008-5472.CAN-14-2788 Google Scholar
  101. 101.
    Arce Vargas F, Furness AJS, Litchfield K, Joshi K, Rosenthal R, Ghorani E, Solomon I, Lesko MH, Ruef N, Roddie C, Henry JY, Spain L, Ben Aissa A, Georgiou A, Wong YNS, Smith M, Strauss D, Hayes A, Nicol D, O'Brien T, Martensson L, Ljungars A, Teige I, Frendeus B, Melanoma TR, Renal TR, consortia TRL, Pule M, Marafioti T, Gore M, Larkin J, Turajlic S, Swanton C, Peggs KS, Quezada SA (2018) Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 33(4):649–663.e4.  https://doi.org/10.1016/j.ccell.2018.02.010 Google Scholar
  102. 102.
    Arlauckas SP, Garris CS, Kohler RH, Kitaoka M, Cuccarese MF, Yang KS, Miller MA, Carlson JC, Freeman GJ, Anthony RM, Weissleder R, Pittet MJ (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9(389):eaal3604.  https://doi.org/10.1126/scitranslmed.aal3604 Google Scholar
  103. 103.
    Hu W, Li X, Zhang C, Yang Y, Jiang J, Wu C (2016) Tumor-associated macrophages in cancers. Clin Transl Oncol 18(3):251–258.  https://doi.org/10.1007/s12094-015-1373-0 Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Center for Cancer Immune Therapy (CCIT), Department of Hematology, Herlev HospitalUniversity of CopenhagenHerlevDenmark
  2. 2.Department of MedicineThe Royal Marsden NHS Foundation TrustLondonUK
  3. 3.Department of Oncology, Herlev HospitalUniversity of CopenhagenHerlevDenmark

Personalised recommendations