Matsushita et al. investigated neoantigen (neoAg) loads in ovarian clear cell carcinoma and found that while neither the number of missense mutations nor the number of predicted neoAgs correlated with improved outcomes, lower neoAg frequency (the number of neoAgs per missense mutation) correlated with a robust immune response and progression-free survival. This suggests that immunoediting of tumor cells with stronger neoantigenic targets had occurred in these patients.
Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes. However, the number of neoantigens per missense mutation ("neoAg frequency") did correlate with clinical outcomes. Cox multivariate regression analysis demonstrated that low neoAg frequencies correlated with increased progression-free survival (PFS) and was an independent predictive factor for PFS in OCCC (p = 0.032), especially at stage I-II (p = 0.0045). Immunity-associated genes including those related to effector memory CD8 T cells were dominantly expressed in tumors with low neoAg frequencies in stage I-II patients, suggesting CD8 T cell-mediated elimination of immunogenic sub-clones expressing neoantigens (immunoediting) had occurred. In contrast, we observed decreased HLA-A, -B, and -C expression (p = 0.036, p = 0.026, and p = 0.030, respectively) as well as increased ratios of CTLA-4, PD-1, Tim-3, and LAG3 to CD8A expression (p = 0.0064, p = 0.017, p = 0.033 and p = 0.0136, respectively) in stage I-II tumors with high neoAg frequencies. Constrained anti-tumor immunity may thus result in limited immunoediting, and poor prognosis. Our results show that neoAg frequency in OCCC is an independent prognostic factor for clinical outcome and may become a potential candidate biomarker for immunomodulatory agent-based treatments.
Author Info: (1) Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan. (2) Department of Gynecologic Oncology, Saitama Medical University International Me
Author Info: (1) Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan. (2) Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan. Gynecologic Oncology Translational Research Unit, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan. (3) Department of Obstetrics and Gynecology, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan. (4) Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan. (5) Department of Obstetrics and Gynecology, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan. (6) Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan. Gynecologic Oncology Translational Research Unit, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan. (7) Department of Obstetrics and Gynecology, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan. (8) Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan. Gynecologic Oncology Translational Research Unit, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan. Department of Obstetrics and Gynecology, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan. (9) Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan. (10) Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan. Gynecologic Oncology Translational Research Unit, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan. (11) Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan. (12) Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.
