Abstract 5026: The association of genomic features and immunosuppression in gastric cancer
Authors: Kumagai Shogo , Togashi Yosuke , Shitara Kohei , Kinoshita Takahiro , Tsuchihara Katsuya , Nishikawa Hiroyoshi 
Published: August 2019

While the clinical efficacy of anti-PD-1 antibody against gastric cancer has been shown, the clinical response is not satisfied. More detailed analyses of immune status in gastric cancer therefore are required. Here, we show that a sub-population of gastric cancer with a specific driver gene mutation develops immunosuppressive tumor microenvironment (TME), not only inhibiting migrations of CD8+ T cells, but also recruiting regulatory T cells (Tregs). The immunological phenotypes of TME were examined with multi-color flow-cytometry and RNA sequencing of surgically resected samples from 22 gastric cancer patients. Gastric cancers were clustered into two groups according to immunologic gene signatures: high- and low-immunogenic tumors. The low-immunogenic group was further divided into two groups with the ratio of effector Tregs to CD4+ T cells ≥20% or &lt; 20%. Among the low-immunogenic group with high effector Tregs to CD4+ T cells ratio (n=5), two patients harbored a specific driver gene mutation. In order to elucidate the detail mechanism by which the specific driver gene mutation in gastric cancer inhibited migrations of CD8+ T cells and recruited Tregs, we evaluated comprehensive gene expressions using the specific driver gene mutation-overexpressed cell lines. Lower expression of chemokines crucial for CD8+ T-cell recruitment (CXCL10) was detected in the specific driver gene mutation-overexpressed cell lines than in the specific driver gene wild-type-overexpressed cell lines. In addition, Gene Set Enrichment Analysis (GSEA) demonstrated enrichment of gene sets associated with fatty acid synthesis in the specific driver gene mutation-overexpressed cell lines compared with the specific driver gene wild-type-overexpressed cell lines. Indeed, abundant fatty acids were detected in TME of driver gene mutation-overexpressed tumors and were dominantly utilized by Tregs, contributing the compelling survival of Tregs in the TME than effector T cells. These results suggested that gastric cancer cells with the specific driver gene mutation reduce the production of chemokines recruiting CD8+ T cells, produce a favorable TME for Tregs. We then developed mouse models and explored TILs and confirmed that the specific driver gene mutation-overexpressed tumors have lower CD8+ T cells and higher Tregs than wild-type-overexpressed tumors. Efficacy of anti PD-1 antibody was ameliorated in the specific driver gene mutation-overexpressed tumors compared with wild-type-overexpressed tumors. Our findings propose that certain types of cancer cells with the specific driver gene mutation inhibit immigration of CD8+ T cells, recruit Tregs, developing an immune suppressive TME associated with the resistance to anti PD-1 antibody. Further studies are required to develop new therapeutic methods of anti PD-1 antibody in combination with inhibitors which block down-streams of the specific driver gene mutation signaling.

Citation Format: Shogo Kumagai, Yosuke Togashi, Kohei Shitara, Takahiro Kinoshita, Katsuya Tsuchihara, Hiroyoshi Nishikawa. The association of genomic features and immunosuppression in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5026.