Dual immune checkpoints inhibition: Cancer treatment and immunological modes of action
Abstract
Programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) are immune checkpoint inhibitors that are effectively esteemed destinations of immunotherapies for the management of melanoma and several cancers. The monotherapy included monoclonal antibodies approved such as Ipilimumab, Pembrolizumab, and Nivolumab planned to restrict with T-cell inhibitory signals to activate the immune responses to cancers. Combined treatment of immune checkpoint blockers can promote results compared to monotherapy in specific patient groups and these clinical advantages can be reported from particular immune mechanisms of action. Although, treatment with checkpoint blockers combinations are present important clinical challenges and raised rates of immune related adverse incidents.
Keywords: Cancer, Checkpoint Inhibitors, T-cell, Immunotherapy, Biomarker
Keywords:
Cancer, Checkpoint Inhibitors, T-cell, Immunotherapy, BiomarkerDOI
https://doi.org/10.22270/jddt.v13i6.5880References
Robbins HA, et al. Melanoma risk and survival among organ transplant recipients. J Invest Dermatol. 2015; 135:2657-2665. https://doi.org/10.1038/jid.2015.312
Shiels MS, et al. Cancer stage at diagnosis in patients infected with the human immunodeficiency virus and transplant recipients. Cancer. 2015; 121:2063-2071. https://doi.org/10.1002/cncr.29324
Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T-cells. J Exp Med. 1996; 183:2533-2540. https://doi.org/10.1084/jem.183.6.2533
Walunas TL, et al. CTLA-4 can function as a negative regulator of T-cell activation. Immunity. 1994; 1:405-413. https://doi.org/10.1016/1074-7613(94)90071-X
Alegre ML, et al. Regulation of surface and intracellular expression of CTLA-4 on mouse T-cells. J Immunol. 1996; 157:4762-4770. https://doi.org/10.4049/jimmunol.157.11.4762
Takahashi T, et al. Immunologic self-tolerance maintained by CD25+ CD4+ regulatory T-cells constitutively expressing cytotoxic T-lymphocyte associated antigen 4. J Exp Med. 2000; 192:303-310. https://doi.org/10.1084/jem.192.2.303
Sansom DM. CD28, CTLA-4 and their ligands: who does what and to whom? Immunology. 2000; 101:169-177. https://doi.org/10.1046/j.1365-2567.2000.00121.x
Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity. 1996; 4:535-543. https://doi.org/10.1016/S1074-7613(00)80480-X
Egen JG, Allison JP. Cytotoxic T-lymphocyte antigen 4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity. 2002; 16:23-35. https://doi.org/10.1016/S1074-7613(01)00259-X
Nishimura H, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice. Science. 2001; 291:319-322. https://doi.org/10.1126/science.291.5502.319
Qureshi OS, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011; 332:600-603. https://doi.org/10.1126/science.1202947
Walker LSK, Sansom DM. Confusing signals: recent progress in CTLA-4 biology. Trends Immunol. 2015; 36:63-70. https://doi.org/10.1016/j.it.2014.12.001
Waterhouse P, et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science. 1995; 270:985-988. https://doi.org/10.1126/science.270.5238.985
Tivol EA, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995; 3:541-547. https://doi.org/10.1016/1074-7613(95)90125-6
Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discovery. 2018; 8:1069-1086. https://doi.org/10.1158/2159-8290.CD-18-0367
Friedline RH, et al. CD4+ regulatory T-cells require CTLA-4 for the maintenance of systemic tolerance. J Exp Med. 2009; 206:421-434. https://doi.org/10.1084/jem.20081811
Read SL, et al. Blockade of CTLA-4 on CD4+ CD25+ regulatory T-cells abrogates their function in vivo. J Immunol. 2006; 177:4376-4383. https://doi.org/10.4049/jimmunol.177.7.4376
Wing K, et al. CTLA-4 control over FoxP3+ regulatory T-cell function. Science. 2008; 322:271-275. https://doi.org/10.1126/science.1160062
Jain N, Nguyen H, Chambers C, Kang J. Dual function of CTLA-4 in regulatory T-cells and conventional T-cells to prevent multiorgan autoimmunity. Proc Natl Acad Sci USA. 2010; 107:1524-1528. https://doi.org/10.1073/pnas.0910341107
Chen H, et al. Anti-CTLA-4 therapy results in higher CD4+ ICO Shi T-cell frequency and IFN-γ levels in both nonmalignant and malignant prostate tissues. Proc Natl Acad Sci. 2009; 106:2729-2734. https://doi.org/10.1073/pnas.0813175106
Wei SC, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell. 2017; 170:1120-1133.e17. https://doi.org/10.1016/j.cell.2017.07.024
Nishikawa H, Sakaguchi S. Regulatory T-cells in tumor immunity. Int J Cancer. 2010; 127:759-767. https://doi.org/10.1002/ijc.25429
Baumgartner J, et al. Melanoma induces immunosuppression by up-regulating FoxP3+ regulatory T-cells. J Surg Res. 2007; 141:72-77. https://doi.org/10.1016/j.jss.2007.03.053
Romano E, et al. Ipilimumab dependent cell-mediated cytotoxicity of regulatory T-cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci USA. 2015; 112:6140-6145. https://doi.org/10.1073/pnas.1417320112
Tarhini AA, et al. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One. 2014; 9:e87705. https://doi.org/10.1371/journal.pone.0087705
Simpson TR, et al. Fc-dependent depletion of tumor infiltrating regulatory T-cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 2013; 210:1695-1710. https://doi.org/10.1084/jem.20130579
Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T-cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009; 206:1717-1725. https://doi.org/10.1084/jem.20082492
Khair DO, et al. Combining immune checkpoint inhibitors: Established and emerging targets and strategies to improve outcomes in melanoma. Front Immunol. 2019; 10:453. https://doi.org/10.3389/fimmu.2019.00453
Vargas FA, et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell. 2018; 33:649-663.e4.
Sharma A, et al. Anti-CTLA-4 immunotherapy does not deplete FoxP3þ regulatory T-cells (Tregs) in human cancers-Response. Clin Cancer Res. 2019; 25:3469-3470. https://doi.org/10.1158/1078-0432.CCR-19-0402
Quezada SA, Peggs KS. Lost in translation: Deciphering the mechanism of action of anti-human CTLA-4. Clin Cancer Res. 2019; 25:1130-1132. https://doi.org/10.1158/1078-0432.CCR-18-2509
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008; 26:677-704. https://doi.org/10.1146/annurev.immunol.26.021607.090331
Yearley JH, et al. PD-L2 expression in human tumors: Relevance to anti-PD-1 therapy in cancer. Clin Cancer Res Off J Am Assoc. Cancer Res. 2017; 23:3158-3167. https://doi.org/10.1158/1078-0432.CCR-16-1761
Agata Y, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B-lymphocytes. Int Immunol. 1996; 8:765-772. https://doi.org/10.1093/intimm/8.5.765
Latchman Y, et al. PD-L2 is a second ligand for PD-1 and inhibits T-cell activation. Nat Immunol. 2001; 2:261-268. https://doi.org/10.1038/85330
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010; 236:219-242. https://doi.org/10.1111/j.1600-065X.2010.00923.x
Yokosuka T, et al. Programmed cell death 1 forms negative costimulatory micro-clusters that directly inhibit T-cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012; 209:1201-1217. https://doi.org/10.1084/jem.20112741
Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999; 11:141-151. https://doi.org/10.1016/S1074-7613(00)80089-8
Simon S, Labarriere N. PD-1 expression on tumor-specific T-cells: Friend or foe for immunotherapy? Oncoimmunology. 2017; 7:e1364828.
https://doi.org/10.1080/2162402X.2017.1364828
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. https://doi.org/10.1111/j.1600-065X.2008.00662.x
Hui E, et al. T-cell costimulatory receptor CD28 is a primary target for PD1-mediated inhibition. Science. 2017; 355:1428-1433. https://doi.org/10.1126/science.aaf1292
Barber DL, et al. Restoring function in exhausted CD8 T-cells during chronic viral infection. Nature. 2006; 439:682-687. https://doi.org/10.1038/nature04444
Huang AC, et al. T-cell invigoration to tumor burden ratio associated with anti-PD-1 response. Nature. 2017; 545:60-65. https://doi.org/10.1038/nature22079
Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T-cells. Int Immunol. 2005; 17:133-144. https://doi.org/10.1093/intimm/dxh194
Hino R, et al. Tumor cell expression of programmed cell death ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010; 116:1757-1766. https://doi.org/10.1002/cncr.24899
Swart M, Verbrugge I, Beltman JB. Combination approaches with immune checkpoint blockade in cancer therapy. Front Oncol. 2016; 6:233. https://doi.org/10.3389/fonc.2016.00233
Marshall HT, Djamgoz MBA. Immuno-oncology: Emerging targets and combination therapies. Front Oncol. 2018; 8:315. https://doi.org/10.3389/fonc.2018.00315
Wei SC, et al. Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc Natl Acad Sci USA. 2019; 116:22699-22709. https://doi.org/10.1073/pnas.1821218116
Curran MA, Montalvo W, Yagita H, Allison JP. 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; 107:4275-4280. https://doi.org/10.1073/pnas.0915174107
Das R, et al. Combination therapy with anti-CTLA-4 and antiPD-1 leads to distinct immunologic changes in vivo. J Immunol. 2015; 194:950-959. https://doi.org/10.4049/jimmunol.1401686
Pedicord VA, Montalvo W, Leiner IM, Allison JP. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci USA. 2011; 108:266-271. https://doi.org/10.1073/pnas.1016791108
Jacquelot N, et al. Immune biomarkers for prognosis and prediction of responses to immune checkpoint blockade in cutaneous melanoma. Oncoimmunology. 2017; 6:1-11. https://doi.org/10.1080/2162402X.2017.1299303
Wolchok JD, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017; 377:1345-1356. https://doi.org/10.1056/NEJMoa1709684
Das R, et al. Early B-cell changes predict autoimmunity following combination immune checkpoint blockade. J Clin Invest. 2018; 128:715-720. https://doi.org/10.1172/JCI96798
Kanjanapan Y, et al. Hyper progressive disease in early phase immunotherapy trials: Clinical predictors and association with immune related toxicities. Cancer. 2019; 125:1341-1349. https://doi.org/10.1002/cncr.31999
Kamada T, et al. PD-1+ regulatory T-cells amplified by PD-1 blockade promote hyper progression of cancer. Proc Natl Acad Sci USA. 2019; 116:9999-10008. https://doi.org/10.1073/pnas.1822001116
Larkin J, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019; 381:1535-1546. https://doi.org/10.1056/NEJMoa1910836
McKinney EF, et al. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature. 2015; 523:612-616. https://doi.org/10.1038/nature14468
Wherry EJ. T-cell exhaustion. Nat Immunol. 2011; 12:492-499. https://doi.org/10.1038/ni.2035
Lee J, Ahn E, Kissick HT, Ahmed R. Reinvigorating exhausted T-cells by blockade of the PD-1 pathway. For Immunopathol Dis Therap. 2015; 6:7-17. https://doi.org/10.1615/ForumImmunDisTher.2015014188
Subudhi SK, et al. Clonal expansion of CD8 T-cells in the systemic circulation precedes development of ipilimumab induced toxicities. Proc Natl Acad Sci USA. 2016; 113:11919-11924. https://doi.org/10.1073/pnas.1611421113
Oh DY, et al. Immune toxicities elicited by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire. Cancer Res. 2017; 77:1322-1330. https://doi.org/10.1158/0008-5472.CAN-16-2324
Lim SY, et al. Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1 based immunotherapy. Clin Cancer Res. 2019; 25:1557-1563. https://doi.org/10.1158/1078-0432.CCR-18-2795
Earnshaw I, et al. Mechanisms of checkpoint inhibition induced adverse events. Clin Exp Immunol. 2020; 200:141-154. https://doi.org/10.1111/cei.13421
Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016; 17:e542-e551. https://doi.org/10.1016/S1470-2045(16)30406-5
Ribas A, Flaherty KT. BRAF targeted therapy changes the treatment paradigm in melanoma. Nat Rev Clin Oncol. 2011; 8:426-433. https://doi.org/10.1038/nrclinonc.2011.69
Luke JJ, Ascierto PA. Biology confirmed but biomarkers elusive in melanoma immunotherapy. Nat Rev Clin Oncol. 2020; 17:198-199. https://doi.org/10.1038/s41571-020-0328-8
Garon EB, et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med. 2015; 372:2018-2028. https://doi.org/10.1056/NEJMoa1501824
Larkin J, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373:23-34. https://doi.org/10.1056/NEJMoa1504030
Robert C, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015; 372:320-330. https://doi.org/10.1056/NEJMoa1412082
Vilain RE, et al. Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma. Clin Cancer Res. 2017; 23:5024-5033. https://doi.org/10.1158/1078-0432.CCR-16-0698
Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer. 2019; 19:133-150. https://doi.org/10.1038/s41568-019-0116-x
Le DT, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 72:2509-2520. https://doi.org/10.1056/NEJMoa1500596
Le DT, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357:409-413. https://doi.org/10.1126/science.aan6733
Tawbi, HA, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018; 379:722-730. https://doi.org/10.1056/NEJMoa1805453
Calabrese LH, Calabrese C, Cappelli LC. Rheumatic immune-related adverse events from cancer immunotherapy. Nat Rev Rheumatol. 2018; 14:569-579. https://doi.org/10.1038/s41584-018-0074-9
Hogan SA, Levesque MP, Cheng PF. Melanoma immunotherapy: Next generation biomarkers. Front Oncol. 2018; 8:178. https://doi.org/10.3389/fonc.2018.00178
Zena NW, et al. Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action. Eur J Immunol. 2021; 51:544-556. https://doi.org/10.1002/eji.202048747
Published
Abstract Display: 347 
PDF Downloads: 469 PDF Downloads: 27 How to Cite
Issue
Section
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
How to Cite
.