J Cancer 2019; 10(12):2754-2763. doi:10.7150/jca.31755

Research Paper

Changes in Expression of Multiple Checkpoint Molecules and Infiltration of Tumor Immune Cells after Neoadjuvant Chemotherapy in Gastric Cancer

Yue Yu1, Xiaopeng Ma2, Yanjuan Zhang2, Yun Zhang2, Jianming Ying3, Wen Zhang1, Qiaofeng Zhong1, Aiping Zhou1,✉, Yixin Zeng4,5,✉

1. Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2. BeiGene (Beijing) Co., Ltd, Beijing, China
3. Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
4. State Key Laboratory of Molecular Oncology, National Cancer Center /National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
5. Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China.

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Citation:
Yu Y, Ma X, Zhang Y, Zhang Y, Ying J, Zhang W, Zhong Q, Zhou A, Zeng Y. Changes in Expression of Multiple Checkpoint Molecules and Infiltration of Tumor Immune Cells after Neoadjuvant Chemotherapy in Gastric Cancer. J Cancer 2019; 10(12):2754-2763. doi:10.7150/jca.31755. Available from http://www.jcancer.org/v10p2754.htm

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Abstract

It remains unclear that how tumor immune micro-environment will change following neoadjuvant chemotherapy (NACT) in locally advanced gastric cancer (LAGC). In this study, we aimed to characterize the changes in tumor-infiltrating immune cells and checkpoint molecules following NACT and investigate the prognostic value of these changes in LAGC. Paired tumor samples (pre-NACT and post-NACT) of 60 patients were retrospectively identified and analyzed by multiplex immunohistochemistry with a panel including CD4, CD8, FOXP3, PD-1, PD-L1, and TIM3. Following NACT, the overall median expression levels of CD4, CD8, PD1, PD-L1 and TIM3 were significantly increased (P = 0.008 for PD-L1 and P < 0.001 for all the other markers), while the median FOXP3 expression level remained stable (P = 0.120). Individually, the majority of patients presented increased expression of the markers, while 8.5%, 11.9%, 16.9%, 25.4%, 22.0% and 42.2% of patients had decreased expression of CD4, CD8, PD-1, PD-L1, TIM3 and FOXP3, respectively. Changes in expression between baseline and post-NACT of TIM3, PD-1, and PD-L1 showed strongly positive pairwise correlations with each other (P < 0.001). Multivariate analysis demonstrated that high upregulation levels of CD8 (HR = 0.73, P = 0.028), PD-1 (HR = 0.76, P = 0.027), and PD-L1 (HR = 0.67, P = 0.038) following NACT were beneficial prognostic factors of OS. NACT increase the expression of multiple checkpoint molecules and infiltration of CD4+, CD8+ immune cells in LAGC with the levels of changes in checkpoint molecules positively related with each other. This may raise the possibility of applying immunotherapy with chemotherapy or even dual checkpoint inhibitors in LAGC.

Keywords: tumor-infiltrating immune cells, checkpoint molecules, neoadjuvant chemotherapy, locally advanced gastric cancer, prognosis