Blood TCTP as a biomarker associated with immunosuppressive features and resistance to immunotherapy in metastatic gastric cancer.

474 Background: Cancer biomarkers are essential for determining the prognosis of the disease and/or predicting its response to specific treatments. However, established biomarkers representing specific myeloid cell populations and representative biomarkers in gastric cancer remain unavailable. Therefore, this study aimed to explore the prognostic and immunological relevance of plasma translationally controlled tumor protein (TCTP) in patients with advanced gastric cancer treated with immune checkpoint inhibitor (ICI) and cytotoxic chemotherapy. Methods: Plasma samples were prospectively collected from the cohorts of patients with gastric cancer who were treated with 1 st line fluoropyrimidine plus platinum chemotherapy (n = 143, cohort 1) and 3 rd line nivolumab (n = 165, cohort 2). Plasma TCTP levels were quantified using ELISA, and multiplex proteomic analysis (Olink) was conducted to assess expression levels of immune-related proteins. An external single-cell RNA sequencing (scRNA-seq) dataset was employed to validate the findings. Results: Patients with high plasma TCTP levels (TCTP-high group) exhibited poor survival outcomes with 1 st line chemotherapy compared to those with low levels (TCTP-low group) in cohort 1. In the TCTP-high group, proteins associated with immunosuppressive myeloid cells, angiogenesis, and immune exclusion of T/NK cell function were upregulated, whereas proteins involved in T-cell activation/exhaustion were significantly upregulated in the TCTP-low group. The scRNA-seq analyses of myeloid cells revealed that TCTP pathway-associated genes (i.e., TLR2 , CXCL1, and CXCL2 ) were specifically expressed in immunosuppressive APOE + macrophages, THBS1 + macrophages, and CD1C + conventional type 2 dendritic cells. In the TCTP-high group, patients treated with nivolumab (cohort 2) also experienced poor survival outcomes. Conclusions: Plasma TCTP is a readily measurable prognostic biomarker, reflecting immunosuppressive signals of myeloid cells in patients with gastric cancer treated with ICI and chemotherapy.