Treating tumors with immune checkpoint inhibitors: Rationale and limitations

Judith Anna Seidel, Atsushi Otsuka, Kenji Kabashima


Immune checkpoints are essential for preventing immunopathology but can also obstruct anti-tumor immune responses. Recent medical advances in blocking these mechanisms have therefore opened promising avenues in the treatment of cancer.  Various blocking antibodies targeting the immune checkpoints programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now approved for human use. This review summarizes the properties of PD-1 and CTLA-4 in physiological and tumor settings, and examines the treatment efficacy, side effects and biomarkers of their inhibitors. Future avenues in the application and development of immune checkpoint inhibitors for the treatment of cancer are also explored.


CTLA-4; PD-1; cancer; immunotherapy; side effects; biomarkers

Full Text:



Chan DV, Gibson HM, Aufiero BM, et al. Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation. Genes Immun 2014; 15(1): 25–32. doi: 10.1038/gene.2013.57.

Leung HT, Bradshaw J, Cleaveland JS, et al. Cytotoxic T lymphocyte-associated molecule-4, a high avidity receptor for CD80 and CD86, contains an intracellular localization motif in its cytoplasmic tail. J Biol Chem 1995; 270(42): 25107–25114. doi: 10.1074/jbc.270.42.25107.

Walker LS, Sansom DM. Confusing signals: Recent progress in CTLA-4 biology. Trends Immunol 2015; 36(2): 63–70. doi: 10.1016/

Pena-Cruz V, McDonough SM, Diaz-Griffero F, et al. PD-1 on immature and PD-1 ligands on migratory human Langerhans cells regulate antigen-presenting cell activity. J Invest Dermatol 2010; 130(9): 2222–2230. doi: 10.1038/jid.2010.127.

Thibult ML, Mamessier E, Gertner-Dardenne J, et al. PD-1 is a novel regulator of human B-cell activation. Int Immunol 2013; 25(2): 129–137. doi: 10.1093/intimm/dxs098.

Lim TS, Chew V, Sieow JL, et al. PD-1 expression on dendritic cells suppresses CD8+ T cell function and antitumor immunity. Oncoimmunology 2016; 5(3): e1085146. doi: 10.1080/2162402X.2015.1085146.

Rodrigues CP, Ferreira AC, Pinho MP, et al. Tolerogenic IDO+ dendritic cells are induced by PD-1-expressing mast cells. Front Immunol 2016; 7: 9. doi: 10.3389/fimmu.2016.00009.

Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003; 33(10): 2706–2716. doi: 10.1002/eji.200324228.

Kinter AL, Godbout EJ, McNally JP, et al. The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008; 181(10): 6738–6746. doi: 10.4049/jimmunol.181.10.6738.

Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25(21): 9543–9553. doi: 10.1128/MCB.25.21.9543-9553.2005.

Patsoukis N, Brown J, Petkova V, et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal 2012; 5(230): ra46. doi: 10.1126/scisignal.2002796.

Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224: 166–182. doi: 10.1111/j.1600-065X.2008.00662.x.

Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2(3): 261–268. doi: 10.1038/85330.

Freeman GJ, Wherry EJ, Ahmed R, et al. Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med 2006; 203(10): 2223–2227. doi: 10.1084/jem.20061800.

Brown JA, Dorfman DM, Ma F-R, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. Journal Immunol 2003; 170(3): 1257–1266. doi: 10.4049/jimmunol.170.3.1257.

Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 1995; 270(5238): 985. doi: 10.1126/science.270.5238.985.

Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008; 322(5899): 271–275. doi: 10.1126/science.1160062.

Nishimura H, Minato N, Nakano T, et al. Immunological studies on PD-1 deficient mice: Implication of PD-1 as a negative regulator for B cell responses. Int Immunol 1998; 10(10): 1563–1572. doi: 10.1093/intimm/10.10.1563.

Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11(2): 141–151. doi: 10.1016/S1074-7613(00)80089-8.

Gough SC, Walker LS, Sansom DM. CTLA4 gene polymorphism and autoimmunity. Immunol Rev 2005; 204: 102–115. doi: 10.1111/j.0105-2896.2005.00249.x.

Nielsen C, Hansen D, Husby S, et al. Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens 2003; 62(6): 492–497. doi: 10.1046/j.1399-0039.2003.00136.x.

Velazquez-Cruz R, Orozco L, Espinosa-Rosales F, et al. Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus. Eur J Hum Genet 2007; 15(3): 336–341. doi: 10.1038/sj.ejhg.5201767.

Kulpa DA, Lawani M, Cooper A, et al. PD-1 coinhibitory signals: The link between pathogenesis and protection. Semin Immunol 2013; 25(3): 219–227. doi: 10.1016/j.smim.2013.02.002.

McMahan RH, Slansky JE. Mobilizing the low-avidity T cell repertoire to kill tumors. Semin Cancer Biol 2007; 17(4): 317–329. doi: 10.1016/j.semcancer.2007.06.006.

Honda Y, Otsuka A, Ono S, et al. Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma. Oncoimmunology 2017; 6(1): e1253657. doi: 10.1080/2162402X.2016.1253657.

Chen J, Feng Y, Lu L, et al. Interferon-γ-induced PD-L1 surface expression on human oral squamous carcinoma via PKD2 signal pathway. Immunobiology 2012; 217(4): 385–393. doi: 10.1016/j.imbio.2011.10.016.

Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 Blockade with pembrolizumab in advanced merkel-cell carcinoma. N Engl J Med 2016; 374(26): 2542–2552. doi: 10.1056/NEJMoa1603702.

Liu C, Workman CJ, Vignali DA. Targeting regulatory T cells in tumors. FEBS J 2016; 283(14): 2731–2748. doi: 10.1111/febs.13656.

Speiser DE, Utzschneider DT, Oberle SG, et al. T cell differentiation in chronic infection and cancer: Functional adaptation or exhaustion? Nat Rev Immunol 2014; 14(11): 768–774. doi: 10.1038/nri3740.

Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 2009; 114(8): 1537–1544. doi: 10.1182/blood-2008-12-195792.

Baitsch L, Baumgaertner P, Devevre E, et al. Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J Clin Invest 2011; 121(6): 2350–2360. doi: 10.1172/JCI46102.

Chapon M, Randriamampita C, Maubec E, et al. Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes. J Invest Dermatol 2011; 131(6): 1300–1307. doi: 10.1038/jid.2011.30.

Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA 2010; 107(9): 4275–4280. doi: 10.1073/pnas.0915174107.

Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271(5256): 1734. doi: 10.1126/science.271.5256.1734.

Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 2003; 100(8): 4712–4717. doi: 10.1073/pnas.0830997100.

Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003; 100(14): 8372–8377. doi: 10.1073/pnas.1533209100.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1): 23–34. doi: 10.1056/NEJMoa1504030.

Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372(26): 2521–2532. doi: 10.1056/NEJMoa1503093.

Abdel-Rahman O, Fouad M. A network meta-analysis of the risk of immune-related renal toxicity in cancer patients treated with immune checkpoint inhibitors. Immunotherapy 2016; 8(5): 665–674. doi: 10.2217/imt-2015-0020.

Chae YK, Chiec L, Mohindra N, et al. A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. Cancer Immunol Immunother 2017; 66(1): 25–32. doi: 10.1007/s00262-016-1913-7.

Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711–723. doi: 10.1056/NEJMoa1003466.

Kato Y, Otsuka A, Miyachi Y, et al. Exacerbation of psoriasis vulgaris during nivolumab for oral mucosal melanoma. J Eur Acad Dermatol Venereol 2016; 30(10): e89–e91. doi: 10.1111/jdv.13336.

Nonomura Y, Otsuka A, Ohtsuka M, et al. ADAMTSL5 is upregulated in melanoma tissues in patients with idiopathic psoriasis vulgaris induced by nivolumab. J Eur Acad Dermatol Venereol 2016; 31: e100–e101. doi: 10.1111/jdv.13818.

Horvat TZ, Adel NG, Dang TO, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 2015; 33(28): 3193–3198. doi: 10.1200/JCO.2015.60.8448.

Della Vittoria Scarpati G, Fusciello C, Perri F, et al. Ipilimumab in the treatment of metastatic melanoma: Management of adverse events. Onco Targets Ther 2014; 7(1): 203–209. doi: 10.2147/OTT.S57335.

Johnston RL, Lutzky J, Chodhry A, et al. Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab. Dig Dis Sci 2009; 54(11): 2538–2540. doi: 10.1007/s10620-008-0641-z.

Freeman-Keller M, Kim Y, Cronin H, et al. Nivolumab in resected and unresectable metastatic melanoma: Characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 2016; 22(4): 886–894. doi: 10.1158/1078-0432.CCR-15-1136.

Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366(26): 2443–2454. doi: 10.1056/NEJMoa1200690.

Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515(7528): 563–567. doi: 10.1038/nature14011.

Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375(19): 1856–1867. doi: 10.1056/NEJMoa1602252.

Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373(2): 123–135. doi: 10.1056/NEJMoa1504627.

Nonomura Y, Otsuka A, Nakashima C, et al. Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients. Oncoimmunology 2016; 5(12): e1248327. doi: 10.1080/2162402X.2016.1248327.

Lu Y, Hong S, Li H, et al. Th9 cells promote antitumor immune responses in vivo. J Clin Invest 2012; 122(11): 4160–4171. doi: 10.1172/JCI65459.

Purwar R, Schlapbach C, Xiao S, et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 2012; 18(8): 1248–1253. doi: 10.1038/nm.2856.

Hoelzinger DB, Dominguez AL, Cohen PA, et al. Inhibition of adaptive immunity by IL9 can be disrupted to achieve rapid T-cell sensitization and rejection of progressive tumor challenges. Cancer Res 2014; 74(23): 6845–6855. doi: 10.1158/0008-5472.CAN-14-0836.

Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372(26): 2509–2520. doi: 10.1056/NEJMoa1500596.

Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348(6230): 124–128. doi: 10.1126/science.aaa1348.

Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014; 371(23): 2189–2199. doi: 10.1056/NEJMoa1406498.

Vetizou M, Pitt JM, Daillere R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; 350(6264): 1079–1084. doi: 10.1126/science.aad1329.

Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 2016; 375(9): 819–829. doi: 10.1056/NEJMoa1604958.

Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation. Immunity 2016; 44(5): 989–1004. doi: 10.1016/j.immuni.2016.05.001.

Leger-Ravet M-B, Mathiot C, Portier A, et al. Increased expression of perforin and granzyme B genes in patients with metastatic melanoma treated with recombinant interleukin-2. Cancer Immunol Immunother 1994; 39(1): 53–58. doi: 10.1007/BF01517181.

Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17(7): 2105–2116. doi: 10.1200/JCO.1999.17.7.2105.

Sim GC, Martin-Orozco N, Jin L, et al. IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J Clin Invest 2014; 124(1): 99–110. doi: 10.1172/JCI46266.

Kodumudi KN, Siegel J, Weber AM, et al. Immune checkpoint blockade to improve tumor infiltrating lymphocytes for adoptive cell therapy. PLoS One 2016; 11(4): e0153053. doi: 10.1371/journal.pone.0153053.

Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350(6264): 1084–1089. doi: 10.1126/science.aac4255.



  • There are currently no refbacks.

Copyright (c) 2017 Judith Anna Seidel

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.