Combination anti–CTLA-4 plus anti–PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies Journal Article
| Authors: | Wei, S. C.; Anang, N. A. A. S.; Sharma, R.; Andrews, M. C.; Reuben, A.; Levine, J. H.; Cogdill, A. P.; Mancuso, J. J.; Wargo, J. A.; Pe’er, D.; Allison, J. P. |
| Article Title: | Combination anti–CTLA-4 plus anti–PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies |
| Abstract: | Immune checkpoint blockade therapy targets T cell-negative costimulatory molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). Combination anti–CTLA-4 and anti–PD-1 blockade therapy has enhanced efficacy, but it remains unclear through what mechanisms such effects are mediated. A critical question is whether combination therapy targets and modulates the same T cell populations as monotherapies. Using a mass cytometry-based systems approach, we comprehensively profiled the response of T cell populations to monotherapy and combination anti–CTLA-4 plus anti–PD-1 therapy in syngeneic murine tumors and clinical samples. Most effects of monotherapies were additive in the context of combination therapy; however, multiple combination therapy-specific effects were observed. Highly phenotypically exhausted cluster of differentiation 8 (CD8) T cells expand in frequency following anti–PD-1 monotherapy but not combination therapy, while activated terminally differentiated effector CD8 T cells expand only following combination therapy. Combination therapy also led to further increased frequency of T helper type 1 (Th1)-like CD4 effector T cells even though anti–PD-1 monotherapy is not sufficient to do so. Mass cytometry analyses of peripheral blood from melanoma patients treated with immune checkpoint blockade therapies similarly revealed mostly additive effects on the frequencies of T cell subsets along with unique modulation of terminally differentiated effector CD8 T cells by combination ipilimumab plus nivolumab therapy. Together, these findings indicate that dual blockade of CTLA-4 and PD-1 therapy is sufficient to induce unique cellular responses compared with either monotherapy. © 2019 National Academy of Sciences. All rights reserved. |
| Keywords: | controlled study; unclassified drug; human cell; cancer combination chemotherapy; drug efficacy; drug potentiation; monotherapy; nonhuman; cancer patient; cd8 antigen; cd8+ t lymphocyte; animal cell; mouse; phenotype; animal tissue; cytotoxic t lymphocyte antigen 4 antibody; ipilimumab; cancer immunotherapy; animal experiment; animal model; cohort analysis; retrospective study; cellular immunity; blood analysis; effector cell; immunomodulation; ctla-4; th1 cell; colon carcinoma; cytotoxic t lymphocyte antigen 4; t lymphocyte subpopulation; t lymphocyte activation; pd-1; programmed death 1 receptor; metastatic melanoma; t cell; programmed death 1 receptor antibody; receptor antibody; immune checkpoint blockade; cellular parameters; nivolumab; human; female; priority journal; article; pembrolizumab; mass cytometry |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 116 |
| Issue: | 45 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2019-11-05 |
| Start Page: | 22699 |
| End Page: | 22709 |
| Language: | English |
| DOI: | 10.1073/pnas.1821218116 |
| PUBMED: | 31636208 |
| PROVIDER: | scopus |
| PMCID: | PMC6842624 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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