The Association between Blood Indexes and Immune Cell Concentrations in the Primary Tumor Microenvironment Predicting Survival of Immunotherapy in Gastric Cancer

SIMPLE SUMMARY: Due to the complexity of the immune response, no single biomarker is available for adequate patient stratification in the context of gastric cancer (GC). In this study, we used multiplexed immunohistochemistry combined with digital image analysis to uncover the immune cell features in 80 patients with GC. Furthermore, we analyzed the association of blood indexes with the primary gastric cancer immune microenvironment. Then, we validated the predicted value of the blood index in a larger GC cohort (n = 357) receiving anti-PD-1/PD-L1 immunotherapy. Importantly, this approach allowed us to map rare cell types with complex phenotypes, characterize the PD-1 and PD-L1 expression intensity in situ, and assess the biomarker value of these parameters and their associations with the blood index. Our data suggest that blood indexes, associated with primary tumor microenvironment, can be used to predict the immune related prognosis in GC. ABSTRACT: The tumor microenvironment plays a vital role in tumor progression and treatment response. However, the association between immune cell concentrations in primary tumor and blood indexes remains unknown. Thus, we enrolled patients with gastric cancer (GC) in two cohorts. We used multiplexed immunohistochemistry to quantify in situ proteins covering rare cell types at sub-cellular resolution in 80 patients with GC in the first cohort. A high correlation between the LMR (lymphocyte-to-monocyte ratio)/NLR (neutrophil-to-lymphocyte ratio) and tumor immune microenvironment was found. The density of exhausted CD8 T cells including CD8(+)PD1(−)TIM3(+), CD8(+)LAG3(+)PD1(+), CD8(+)LAG3(+)PD1(−), CD8(+)LAG3(+)PD1(+)TIM3(−) was negatively associated with LMR and positively associated with NLR (p < 0.05). Additionally, the higher density of macrophages in tumor core was associated with a higher platelet-to-lymphocyte ratio and systemic immune-inflammation index. Furthermore, we validated the prognostic value of LMR and NLR in an independent cohort of 357 gastric cancer patients receiving immunotherapy. Higher LMR at baseline was significantly associated with superior immune-related PFS (irPFS) and a trend of superior immune-related OS (irOS). Higher NLR was associated with inferior irOS. In conclusion, blood indexes were associated with immune cells infiltrating in primary tumors of GC. NLR and LMR are associated with the density of exhausted CD8(+) T immune cells, which leads to prognostic values of immunotherapy.