Immune checkpoint therapy with antibodies targeting CTLA4 or PD1/PDL1 has led to durable regression of disease and cures for a subset of patients with cancer, which has led to increased efforts to develop combination immunotherapy strategies to benefit an even greater number of patients. However, questions remain as to which combinations should be used and in which population of patients. In 2019, several studies reported on the differential impact of targeting CTLA4 and/or PD1 on T cell responses, with clear evidence that both CD4+ and CD8+ T cell responses are needed. These data highlight the complementary nature of targeting CTLA4 and PD1 to drive both CD4+ and CD8+ effector T cell responses, which should be considered in future treatment strategies. Furthermore, reverse translational studies, which provide immune response data from patients receiving immune checkpoint therapy, have revealed resistance mechanisms that indicate relevant targets for combination strategies. Taken together, future treatments will likely consist of anti-CTLA4 plus anti-PD1 with addition of individualized therapy on the basis of tumour type and site of metastatic disease.
Key advances
Genetic deletion of CTLA4 in mice leads to the development of noncanonical subsets of ICOS+CD4+ effector T cells, whereas genetic deletion of PD1 leads to only subtle changes in CD8+ T cells, including an increase in frequency of PD1hiTIM3hiLAG3hi ‘exhausted’ CD8+ T cells.
Combination therapy with anti-CTLA4 plus anti-PD1 monocolonal antibodies leads to predictable changes such as an increased frequency of ICOS+CD4+ effector T cells but also leads to unexpected and unique changes including a decreased frequency of exhausted CD8+ T cells and the expansion of activated CD8+ effector T cells.
CD4+ and CD8+ T cell responses are impacted differentially by anti-CTLA4 and anti-PD1 therapy, respectively, and combination therapy enhances both effector CD4+ and CD8+ T cell responses.
Organ-specific tumour niches can impact response to immune checkpoint therapy.
Reverse translational studies, which start with human data and lead to the generation of hypotheses that are tested in appropriate preclinical models, will provide crucial data regarding response and resistance mechanisms to immune checkpoint therapy in patients.
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Acknowledgements
The authors thank members of their team, especially S. Goswami, S. Wei and S. Anandhan, for critical reading and helpful suggestions for this manuscript.
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P.S. and J.P.A. consult for and/or have equity in Jounce, Neon, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Dragonfly, Lytix, Lava Therapeutics, Achelois and Hummingbird. P.S. also consults for and/or has equity in Constellation and Oncolytics. J.P.A. also consults for and has equity in Tvardi Therapeutics.
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Sharma, P., Allison, J.P. Dissecting the mechanisms of immune checkpoint therapy. Nat Rev Immunol 20, 75–76 (2020). https://doi.org/10.1038/s41577-020-0275-8
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DOI: https://doi.org/10.1038/s41577-020-0275-8
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