Crosby et al. looked to understand the mechanism of combined anti-PD-1 and anti-CTLA-4 immune checkpoint blockade (ICB) therapy in an orthotopic triple-negative breast cancer (TNBC) model designed to mimic the immunologic characteristics of human TNBC. Anti-PD-1 relief of PD-L1-based immunosuppression was dramatically enhanced in conjunction with anti-CTLA-4, which both broadened the T-cell repertoire (as measured by TCR sequencing) and eliminated intratumoral Tregs. A profound antitumor response was only observed when both therapies were combined.

Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (0%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB. While promising, these modest response rates highlight the need for mechanistic studies to understand how different ICBs function, how their combination impacts functionality and efficacy, as well as what immunologic parameters predict efficacy to different ICBs regimens in TNBC. To address these issues, we tested anti-PD1 and anti-CTLA4 in multiple models of TNBC and found that their combination profoundly enhanced the efficacy of either treatment alone. We demonstrate that this efficacy is due to anti-CTLA4-driven expansion of an individually unique T-cell receptor (TCR) repertoire whose functionality is enhanced by both intratumoral Treg suppression and anti-PD1 blockade of tumor expressed PDL1. Notably, the individuality of the TCR repertoire was observed regardless of whether the tumor cells expressed a nonself antigen (ovalbumin) or if tumor-specific transgenic T-cells were transferred prior to sequencing. However, responsiveness was strongly correlated with systemic measures of tumor-specific T-cell and B-cell responses, which along with systemic assessment of TCR expansion, may serve as the most useful predictors for clinical responsiveness in future clinical trials of TNBC utilizing anti-PD1/anti-CTLA4 ICB.

Author Info: (1) Department of Surgery, Duke University, Durham, NC, United States. (2) Department of Surgery, Duke University, Durham, NC, United States. (3) Department of Surgery, Duke

Author Info: (1) Department of Surgery, Duke University, Durham, NC, United States. (2) Department of Surgery, Duke University, Durham, NC, United States. (3) Department of Surgery, Duke University, Durham, NC, United States. (4) Department of Surgery, Duke University, Durham, NC, United States. (5) Department of Surgery, Duke University, Durham, NC, United States. (6) Department of Surgery, Duke University, Durham, NC, United States. (7) Department of Surgery, Duke University, Durham, NC, United States. (8) Immuno-Oncology Discovery, Bristol-Myers Squibb Company, Redwood City, CA, United States. (9) Department of Surgery, Duke University, Durham, NC, United States. Department of Medicine, Duke University, Durham, NC, United States. (10) Department of Biomedical Sciences, Cedars-Sinai Medical Institute, Los Angeles, CA, United States. (11) Department of Biomedical Sciences, Cedars-Sinai Medical Institute, Los Angeles, CA, United States. (12) Department of Surgery, Duke University, Durham, NC, United States. Department of Pathology/Immunology, Duke University, Durham, NC, United States. (13) Department of Surgery, Duke University, Durham, NC, United States.

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