Abstract 6498: Preoperative treatment remodels immune microenvironment via decreasing pro-tumorigenic and increasing anti-tumorigenic immune cells in the locally advanced gastric cancer
Authors: Fang Yi , Zhang Yujing , Li Nai , Ling Yihong , Zhou Zhiwei 
Published: September 2020

Abstract
Purpose: To investigate the immune response in the tumor microenvironment and the association between immune response and pathological response after preoperative chemotherapy or preoperative chemoradiotherapy for locally advanced gastric cancer.
Experimental Design:123 patients with locally advanced gastric cancer with or without preoperative treatment were analyzed by immunohistochemistry for CD4, CD45RO, FOXP3 and PD-L1. 83 of the 123 patients completed preoperative treatment and radical gastrectomy in our hospital between June 2013 and September 2019, which belonged to an ongoing multicentric randomized phase III clinical trial comparing preoperative chemoradiation with preoperative chemotherapy in patients with locally advanced gastric cancer (NCT01815853). They were 41 patients in the preoperative chemoradiotherapy (CRT) group, and 42 patients in the preoperative chemotherapy (ChT) group. The other 40 patients underwent surgery first without preoperative treatment (Surgery First group: SF) matched according to clinical pathological characteristics with the CRT and ChT group. T-cell subset densities both within tumor area and at the invasive front were analyzed using slide digital imaging and automated and software-based quantification algorithms. Pathological response of primary tumor was analyzed according to the NCCN tumor regression grade (TRG). The differences of T-cell subset densities and PD-L1 status among three groups and the relationship between these differences and tumor regression was evaluated.
Results: The patients’ baseline and tumor characteristics were well-balanced among CRT, ChT, and SF groups. 28 patients obtained TRG0-2 in CRT group (n=41), in contrast, only 18 patients obtained TRG0-2 in ChT group (n=42; P=0.020). The number of FOXP3+ T cell and CD45RO+ T cell infiltrations was significantly lower in the CRT group (tumor area: P&lt;0.001, P=0.011 respectively; invasive front: P&lt;0.001, P&lt;0.001 respectively) or ChT group (tumor area: P&lt;0.001, P=0.033 respectively; invasive front: P&lt;0.001, P=0.001 respectively) comparing with SF group. In contrast, the number of CD8+ T cells in tumor invasive front was significant higher in the CRT group (P&lt;0.001) or ChT group (P=0.002) comparing with SF group. Addition of radiation to preoperative chemotherapy (CRT) significantly decreased PD-L1 expression in tumor cells (CRT group vs. ChT group: 14.6% vs. 35.7%, P=0.027). However, no differences of T cell infiltrations and PD-L1 expression in immune cells between CRT group and ChT group were observed. In CRT group, lower FOXP3+ cell density in tumor area (P&lt;0.001) and invasive front (P=0.009), higher CD8+ cell density (P=0.040) and CD45RO+ T cell density (P=0.045) in tumor area were strongly associated with higher probability of achieving TRG0-2. In ChT group, lower FOXP3+ cell density in tumor area (P=0.027) and higher CD8+ cell density (P=0.040) in invasive front were significantly associated with higher probability of achieving TRG0-2.
Conclusions: Preoperative treatment in locally advanced gastric cancer is useful for reducing regulatory T cell levels and increasing cytotoxic T cell levels. CRT and ChT may not only be cytotoxic, but have pleiotropic and beneficial effects on the tumor microenvironment.
Citation Format: Yi Fang, Yujing Zhang, Nai Li, Yihong Ling, Zhiwei Zhou. Preoperative treatment remodels immune microenvironment via decreasing pro-tumorigenic and increasing anti-tumorigenic immune cells in the locally advanced gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6498.