Abstract
BackgroundDefects in DNA damage repair (DDR) system may lead to genomic instability and manifest as increased immunogenicity. DDR deficiency is prevalent in ovarian cancer (OvCa); however, the association of DDR mutation with immune profiles in OvCa remains largely unknown. This knowledge will provide an essential basis to the rational design of biomarker‐guided immune combination therapy of OvCa in the future.MethodsWhole‐exome sequencing data of 587 OvCa from The Cancer Genome Atlas (TCGA) were used to determine the expression profiles of 47 immune‐related genes and the abundance of tumor‐infiltrating immune cells. A Chinese OvCa cohort (n = 220) tested by next‐generation sequencing (NGS) was used to validate the association between DDR status and tumor mutation burden (TMB).ResultsA total of 19.3% in TCGA cohort and 25.9% in Chinese cohort harbored at least one DDR somatic mutation. DDR deficiency exhibited a distinct immune profile with significant higher expression levels of PTPRCAP, CCL5, IFI16, LAG3, IL15RA, and GBP1 in OvCa in the TCGA cohort. Different DDR pathway deficiency displayed various immune profiles. Increased levels of Th1 cells, TMB, and neoantigen were also observed in DDR‐deficient tumors.ConclusionsDDR deficiency was associated with specific immune signatures in OvCa. Our findings emphasize the urgent need for biomarker‐guided rational immune combination therapy to maximize the OvCa patients who could benefit from immunotherapy.
Highlights
Ovarian cancer (OvCa) remains the leading cause of death among gynecological cancers.[1]
We revealed that ovarian cancer (OvCa) with somatic DNA damage repair (DDR) mutation manifested as a distinct immune profile with higher expression levels of PTPRCAP, CCL5, IFI16, LAG3, IL15RA, and GBP1
Increasing levels of Th1 cell abundance, tumor mutation burden (TMB), and neoantigen were observed in OvCa with somatic DDR mutation
Summary
Ovarian cancer (OvCa) remains the leading cause of death among gynecological cancers.[1]. Promising biomarkers and rational immune combination therapies are needed to maximize patients with OvCa who could benefit from immunotherapy. A study has revealed that co-mutations in specific DDR pathways might predict clinical benefit from ICIs treatment.[18]. Another study further verified the association between alterations in 34 DDR genes exhibited a higher TMB level and improved clinical benefit from ICIs in urothelial cancer.[19]. This knowledge will provide essential basis to the design of biomarker-guided rational immune combination therapy in the future To validate this hypothesis, we interrogated the expression profiles of 47 immune-related gene panel using the sequencing data from The Cancer Genome Atlas (TCGA) (n = 587) to characterize the pattern of DDR mutations and investigate their association with the expression profiles of immune-related genes in OvCa
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