Mandal and Samstein et al. investigated the variable response to anti-PD-1 in patients with mismatch repair-deficient (MMR-d) tumors. Quantification of microsatellite instability (MSI) in both MSH2 knockout murine tumor cell lines and patients with MMR-d tumors revealed a range of MSI intensity (and consequent mutation load). Responses to anti-PD-1 were associated with high MSI scores, and in particular, an accumulation of insertion-deletion (indel) mutations. An analysis of murine tumor genomes supported evolution through immunoediting. Genome-wide characterization of MSI intensity may help predict responses to anti-PD-1 in MMR-d patients.
Tumors with mismatch repair deficiency (MMR-d) are characterized by sequence alterations in microsatellites and can accumulate thousands of mutations. This high mutational burden renders tumors immunogenic and sensitive to programmed cell death-1 (PD-1) immune checkpoint inhibitors. Yet, despite their tumor immunogenicity, patients with MMR-deficient tumors experience highly variable responses, and roughly half are refractory to treatment. We present experimental and clinical evidence showing that the degree of microsatellite instability (MSI) and resultant mutational load, in part, underlies the variable response to PD-1 blockade immunotherapy in MMR-d human and mouse tumors. The extent of response is particularly associated with the accumulation of insertion-deletion (indel) mutational load. This study provides a rationale for the genome-wide characterization of MSI intensity and mutational load to better profile responses to anti-PD-1 immunotherapy across MMR-deficient human cancers.
Author Info: (1) Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD 21287, USA. Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Ba
Author Info: (1) Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD 21287, USA. Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (5) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (6) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (7) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (8) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (9) Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (10) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (11) Department of Otolaryngology-Head and Neck Surgery, Weill Cornell New York Presbyterian Hospital, New York, NY 10065, USA. (12) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. (13) Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. (14) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (15) Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (16) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (17) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (18) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (19) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (20) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (21) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (22) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. (23) Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (24) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. chant@mskcc.org. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
