In a patient with advanced prostate cancer, pembrolizumab resulted in CR and, followed by a radical prostatectomy, prevented recurrence out to 18mo. Tumor whole-exome NGS indicated dMMR/MSI-H and an extremely high TMB. Among PBMCs, CD56+ NK-like CD8+ T cells and CD4+CD8+ double-positive (DP) T cells were observed at high frequency relative to healthy donors, expressed cytotoxic/effector gene signatures and TEMRA phenotype, and clonally expanded after ICB. In other trials (prostate and dMMR/MSI-H cancers), CD56+CD8+ and DP T cells were found among TILs in ICB-treated patients, and DP T cell expansion was positively associated with patient response.
Contributed by Alex Najibi
ABSTRACT: Mismatch repair deficiency (dMMR) and microsatellite instability (MSI-H) are rare in prostate cancer, occurring in 2%-4% of cases. These defects result in increased genomic instability and elevated tumor mutational burden (TMB), which can support responses to immune checkpoint inhibitors (ICIs). Here, we report a patient with locally advanced Gleason 5 + 5 = 10 prostatic adenocarcinoma harboring MSH2 and MSH6 genomic deletions with ultrahigh TMB (>250 mutations/megabase) in whom pembrolizumab resulted in a striking complete radiographic, pathologic, and molecular response. Using digital-spatial microscopy, single-cell RNA/T cell receptor (TCR) sequencing, and multiplex cytometry, we identify atypical tumor-infiltrating T cells with natural killer-like phenotypes and CD4(+)CD8(+) (double-positive) lymphocytes. These clonal T cell populations expand preferentially following ICI and adopt terminally differentiated and cytotoxic profiles that may drive clinical response. Similar T cells are also present in diverse cancers and expand exclusively in ICI-responsive patients. These findings inform on the cellular mechanisms by which immunotherapies may mediate profound responses in patients with dMMR solid tumors.
Author Info: (1) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesot
Author Info: (1) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (2) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (3) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (4) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (5) Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA; Clinical Translational Science Institute, University of Minnesota, Minneapolis, MN 55415, USA. (6) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (7) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (8) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (9) Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA. (10) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (11) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (12) Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. (13) Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (14) Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (15) Caris Life Sciences, Phoenix, AZ 85040, USA. (16) Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA. (17) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (18) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (19) Allina Health Cancer Institute, Minneapolis, MN 55407, USA. (20) Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA. (21) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (22) Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA; Clinical Translational Science Institute, University of Minnesota, Minneapolis, MN 55415, USA. (23) Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. (24) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (25) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (26) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (27) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: anton401@umn.edu.
