Cillo et al. analyzed samples from patients in an ongoing trial comparing relatlimab (anti-LAG3), nivolumab (anti-PD-1), and the combination of the two. Anti-LAG3 alone induced increased TCR signaling and exhaustion in emergent clones, anti-PD-1 alone induced IFNγ signaling and decreased exhaustion, and the combination of the two altered CD8+ T cell differentiation and enhanced responses to both TCR and IFNγ signaling, despite T cells maintaining an apparent exhaustion profile. The effects of the combination were driven by PRDM1, BATF, ETV7, and TOX, and were associated with CD38/TIM3 expression and better clinical outcomes.
Contributed by Lauren Hitchings
ABSTRACT: Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8(+) T cell receptor signaling and altered CD8(+) T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8(+) T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8(+) T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38(+)TIM3(+)CD8(+) T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: arc85@pitt.edu. (2) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (3) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Integrative Systems Biology (ISB) Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (4) Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (5) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (6) Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (7) Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (8) Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (9) Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (10) Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (11) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (12) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: kirkwoodjm@upmc.edu. (13) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: tbruno@pitt.edu. (14) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: dvignali@pitt.edu.
