title: Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer.
abstract: Immune checkpoint inhibitors (e.g., anti-PD-1 and anti-PD-L1 antibodies) have demonstrated remarkable efficacy against hypermutated cancers such as melanomas and lung carcinomas. One explanation for this effect is that hypermutated lesions harbor more tumor-specific neoantigens that stimulate recruitment of an increased number of tumor-infiltrating lymphocytes (TILs), which is counterbalanced by overexpression of immune checkpoints such as PD-1 or PD-L1. Given that BRCA1/2-mutated high grade serous ovarian cancers (HGSOCs) exhibit a higher mutational load and a unique mutational signature with an elevated number of larger indels up to 50 bp, we hypothesized that they may also harbor more tumor-specific neoantigens, and, therefore, exhibit increased TILs and PD-1/PD-L1 expression. Here, we report significantly higher predicted neoantigens in BRCA1/2-mutated tumors compared to tumors without alterations in homologous recombination (HR) genes (HR-proficient tumors). Tumors with higher neoantigen load were associated with improved overall survival and higher expression of immune genes associated with tumor cytotoxicity such as genes of the TCR, the IFN-gamma and the TNFR pathways. Furthermore, immunohistochemistry studies demonstrated that BRCA1/2-mutated tumors exhibited significantly increased CD3+ and CD8+ TILs, as well as elevated expression of PD-1 and PD-L1 in tumor-associated immune cells compared to HR-proficient tumors. Survival analysis showed that both BRCA1/2-mutation status and number of TILs were independently associated with outcome. Of note, two distinct groups of HGSOCs, one with very poor prognosis (HR proficient with low number of TILs) and one with very good prognosis (BRCA1/2-mutated tumors with high number of TILs) were defined. These findings support a link between BRCA1/2-mutation status, immunogenicity and survival, and suggesting that BRCA1/2-mutated HGSOCs may be more sensitive to PD-1/PD-L1 inhibitors compared to HR-proficient HGSOCs.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Strickland
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Howitt
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Sachet A
authors.initials: SA
authors.lastname: Shukla
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Ritterhouse
authors.affiliation: Medical Gynecologic Oncology Program, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.affiliation: Division of Genomic Stability and DNA Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Division of Genomic Stability and DNA Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.affiliation: Medical Gynecologic Oncology Program, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.affiliation: Medical Gynecologic Oncology Program, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Panagiotis A
authors.initials: PA
authors.lastname: Konstantinopoulos
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism*; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D059765:Homologous Recombination; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: BRCA1 and BRCA2 mutations; PD-1 and PD-L1; high grade serous ovarian cancer; homologous recombination DNA repair; immunogenicity