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Simple Summary: There is a lack of biomarkers for predicting the response to chemotherapy in gastric cancer (GC). This study investigates the prognostic significance of PD-1 expression in CD8+ T cells in the blood of 68 patients with advanced GC receiving platinum-based chemotherapy. Patients were divided based on baseline frequencies of PD-1+CD8+ T cells and whether these frequencies increased or decreased on day 7 after treatment. While baseline frequencies of PD-1+CD8+ T cells had no impact on survival, the patients whose frequencies of PD-1+CD8+ T cells increased on day 7 from the treatment initiation showed significantly longer survival than those whose frequencies of PD-1+CD8+ T cells decreased. This difference was also reflected in the mean duration of response between the groups. These findings suggest that an early increase in frequencies of PD-1+CD8+ T cells could predict favorable prognoses and durable responses in patients with advanced GC receiving chemotherapy. The clinical significance of PD-1 expression in circulating CD8+ T cells in patients with gastric cancer (GC) receiving chemotherapy remains unelucidated. Therefore, we aimed to examine its prognostic significance in blood samples of 68 patients with advanced GC who received platinum-based chemotherapy. The correlation between peripheral blood mononuclear cells, measured using fluorescence-activated cell sorting, was evaluated. Patients were divided into two groups according to the changes in PD-1+CD8+ T-cell frequencies between day 0 and 7. They were categorized as increased or decreased PD-1+CD8+ T-cell groups. The increased PD-1+CD8+ T-cell group showed longer progression-free survival (PFS) and overall survival (OS) than the decreased PD-1+CD8+ T-cell group (PFS: 8.7 months vs. 6.1 months, p = 0.007; OS: 20.7 months vs. 10.8 months, p = 0.003). The mean duration of response was significantly different between the groups (5.7 months vs. 2.5 months, p = 0.041). Multivariate analysis revealed that an increase in PD-1+CD8+ T-cell frequency was an independent prognostic factor. We concluded that the early increase in PD-1+CD8+ T-cell frequency is a potential predictor of favorable prognoses and durable responses in patients with advanced GC receiving chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent studies have sought to evaluate early oncogenic signaling in EGFR-mutant lung cancers under EGFR-TKI treatment, but few studies have evaluated the effect of the tumor microenvironment on persistent tumor cells under EGFR-TKI treatment. Our study demonstrates that CXCL10, a representative inflamed immune-response cytokine, activates CXCR3 in tumor cells to induce the phosphorylation of Src and the NF-κB subunit, p65, and the expression of HIF1-α in persistent EGFR-mutant tumor cells during EGFR-TKI treatment. We further reveal that the CXCL10/CXCR3 signaling of tumor cells is augmented via an autocrine pathway. Our study reveals that the EGFR-TKI-treatment-related oncogenic pathway changes contributing to EGFR-TKI resistance in EGFR-mutant NSCLC are paradoxically attributed to the targeting of tumor cells by an activated immune system. CXCL10 is a cytokine that is elevated during EGFR-TKI treatment in the tumor microenvironment of lung cancer. Here, we report an original study that the impact of the CXCL10/CXCR3 pathway on EGFR-TKI resistance in EGFR-mutant lung cancer through a cytokine array analysis during in vitro coculture with tumor cells and activated PBMCs treated with EGFR-TKI, as well as the serial analysis of CXCL10 in EGFR-mutant lung cancer transgenic mice during EGFR-TKI treatment. In EGFR-mutant tumor cells cocultured with activated PBMCs, EGFR-TKI treatment increased CXCL10 in the supernatant; this activated CXCR3 in the tumor cells to induce the phosphorylation of Src and the NF-κB subunit, p65, and the expression of HIF-1α. CXCL10 siRNA treatment of EGFR-mutant tumor cells also decreased CXCL10 in the supernatant from coculturing with activated PBMCs, suggesting that the effects of CXCL10 occur via autocrine and paracrine pathways. Importantly, elevated CXCL10/CXCR3 signaling was recapitulated in a transgenic lung cancer mouse model. Our results show that increased CXCL10 levels during early EGFR-TKI treatment stimulate oncogenic signaling of persistent tumor cells to contribute to EGFR-TKI resistance via autocrine and paracrine pathways. [ABSTRACT FROM AUTHOR]