Abstract
BackgroundGenetic alterations have been proven to be the promising biomarkers for ICI response. However, sex biases in genetic alterations have been often ignored in the field of immunotherapy, which might specially influence the anticancer immunity and immunotherapy efficacy in male or female patients. Here, we have systematically evaluated the effect of the sex biases in somatic mutation of gastric cancer (GC) patients on the anticancer immunity and clinical benefit to immunotherapy.MethodsGenomic and transcriptomic data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). We also obtained the genomic and clinical data of a MSKCC ICI-treated cohort from cbioportal database. GC male and female-derived tumor somatic mutation profiles were compared by maftools R package. Single sample gene set enrichment analysis (ssGSEA) was conducted to calculate the score of the anticancer immunity indicators including IFN-γ signaling, cytolytic activity (CYT) and antigen presenting machinery (APM).ResultsATRX was found to mutate more frequently in female GC patients compared to male patients (FDR = 0.0108). Female GC patients with ATRX mutation manifested significantly more MSI-high subtypes, increased TMB and PDL1 expression as well as higher scores of IFN-γ signaling, CYT and APM. Gene set enrichment analysis (GSEA) has shown that ATRX mutation might enhance the immunogenicity and anticancer immunity through affecting DNA damage repair pathways. In the ICI-treated cohort from MSKCC, GC patients with ATRX mutation were associated with prolonged overall survival. When stratifying the entire ICI-treated cohort by sex, female patients with ATRX mutation obtained significantly better survival benefits than that of ATRX mutant male patients (Female patients, HR of ATRX MT vs WT = 0.636, 95%CI = 0.455–0.890, P = 0.023; Male patients, HR of ATRX MT vs WT = 0.929, 95%CI = 0.596–1.362, P = 0.712).ConclusionsATRX mutation might serve as a potential predictive biomarker for favorable clinical benefit to ICI in female GC patients. ATRX mutation could be applied in combination with other biomarkers of ICI response to better identify the female GC patients who will derive greater benefits from ICI therapy.
Highlights
Genetic alterations have been proven to be the promising biomarkers for immune checkpoint inhibitors (ICI) response
We systematically evaluated the sex variance in gastric cancer (GC) somatic mutation profiles and discovered that ATRX mutation more frequently occurring in female GC patients was associated with higher Tumor mutation burden (TMB), increased anticancer immunity and favorable clinical benefit to ICI
In this study, through comparing somatic mutation profiles derived from male and female GC patients, we identified for the first time that the ATRX mutation preferentially occurred in female GC patients was associated with higher TMB, increased anticancer immunity and favorable clinical benefit to ICI
Summary
Genetic alterations have been proven to be the promising biomarkers for ICI response. Sex biases in genetic alterations have been often ignored in the field of immunotherapy, which might specially influence the anticancer immunity and immunotherapy efficacy in male or female patients. The development of tumor immunotherapy, represented by immune checkpoint inhibitors (ICI), has reshaped the treatment of solid tumors and proven efficacy in some malignancy, such as melanoma, non-small cell lung cancer, renal cell carcinoma and recurrent squamous cell carcinoma of the head and neck [2,3,4,5]. ICIs have shown encouraging preliminary efficacy in advanced GC, the overall response to ICI might not be as remarkable as to those solid tumors such as melanoma and non-small cell lung cancer [6]. Further GC researches on development of accurate biomarkers that can predict the response to ICI are mandatory
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