Raghavan et al. showed variable, but comparable reduction of MC38 tumor growth in constitutive PD-1 KO mice, mice genetically engineered to induce Pdcd1 deletion on demand during tumor growth, and anti-PD-1 antibody-treated WT mice. All mice that had complete primary tumor regression exhibited a specific memory response upon tumor rechallenge. Flow and mass cytometric and gene expression analyses of TILs showed that PD-1 blockade or deletion expanded activated IFNγ+granzyme B+ICOS+CD8+ effector/memory and cytotoxic TILs and granzyme B+CD4+ effector/memory TILs, and reduced Foxp3+CD4+ TILs, concordant with tumor tissue RNA analyses.
Contributed by Paula Hochman
ABSTRACT: Programmed cell death-1 (PD-1) blockade has a profound effect on the ability of the immune system to eliminate tumors, but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following inhibition of PD-1 signaling was investigated in the MC-38 colon carcinoma model using constitutive (PD-1 KO) and conditional (PD1cKO) mice and in wild-type mice treated with PD-1 antibody. The impact on both tumor growth and the development of tumor immunity was assessed. In the PD-1cKO mice, a complete deletion of Pdcd1 in tumor-infiltrating T cells (TILs) after tamoxifen treatment led to the inhibition of tumor growth of both small and large tumors. Extensive immune phenotypic analysis of the TILs by flow and mass cytometry identified 20-different T cell subsets of which specifically 5-CD8 positive ones expanded in all three models after PD-1 blockade. All five subsets expressed granzyme B and interferon gamma (IFN_). Gene expression analysis of the tumor further supported the phenotypic analysis in both PD-1cKO- and PD-1 Ab-treated mice and showed an upregulation of pathways related to CD4 and CD8 T-cell activation, enhanced signaling through costimulatory molecules and IFN_, and non-T-cell processes. Altogether, using PD-1cKO mice, we define the intrinsic nature of PD-1 suppression of CD8 T-cell responses in tumor immunity.
Author Info: (1) Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States. Department of Microbiology and Immunology, Institute for Biomedicine, University of Gothenburg, Gothe
Author Info: (1) Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States. Department of Microbiology and Immunology, Institute for Biomedicine, University of Gothenburg, Gothenburg, Sweden. (2) Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States. (3) Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States. (4) Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States. (5) Centre d'Immunophnomique - CIPHE (PHENOMIN), Aix Marseille Universit (UMS3367), National Institute of Health and Medical Research (INSERM) (US012), The French National Centre for Scientific Research (CNRS) (UMS3367), Marseille, France. (6) Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States. (7) Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States. (8) Merck & Co., Inc., Boston, MA, United States. (9) Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States. (10) Merck & Co., Inc., Boston, MA, United States. (11) Merck & Co., Inc., Kenilworth, NJ, United States. (12) Centre d'Immunophnomique - CIPHE (PHENOMIN), Aix Marseille Universit (UMS3367), National Institute of Health and Medical Research (INSERM) (US012), The French National Centre for Scientific Research (CNRS) (UMS3367), Marseille, France. (13) Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States.
