CD8+ T cells are a major prognostic determinant in solid tumors, including colorectal cancer (CRC). However, understanding how the interplay between different immune cells impacts on clinical outcome is still in its infancy. Here, we describe that the interaction of tumor infiltrating neutrophils expressing high levels of CD15 with CD8+ T effector memory cells (TEM) correlates with tumor progression. Mechanistically, stromal cell-derived factor-1 (CXCL12/SDF-1) promotes the retention of neutrophils within tumors, increasing the crosstalk with CD8+ T cells. As a consequence of the contact-mediated interaction with neutrophils, CD8+ T cells are skewed to produce high levels of GZMK, which in turn decreases E-cadherin on the intestinal epithelium and favors tumor progression. Overall, our results highlight the emergence of GZMKhigh CD8+ TEM in non-metastatic CRC tumors as a hallmark driven by the interaction with neutrophils, which could implement current patient stratification and be targeted by novel therapeutics.

Purpose Despite immune checkpoint inhibitor (ICI) has recently taken on an extremely important role in tumors, only a minority of hepatocellular carcinoma (HCC) patients are effective. The clinical value of PRC1 and DLGAP5 in HCC and its relationship with immune microenvironment have been rarely reported. Methods Key genes related to doubling time of HCC tumors were identified using WGCNA, and their expression was analyzed against our in-house RNA sequencing database, the Gene Expression Omnibus and the Cancer Genome Atlas database. We explored correlations between key genes and the immune microenvironment based on the TISCH and TIMER database, as well as clinicopathological characteristics and prognosis of HCC in patients at our center. Results WGCNA identified PRC1 and DLGAP5 as key genes in HCC. PRC1 and DLGAP5 were over-expressed in HCC tissues relative to normal tissues based on analysis of 2,154 patients and 1,344 controls. The genes gave respective areas under the summary receiver operator characteristic curve of 0.95 (95%CI 0.93–0.97) and 0.94 (95%CI 0.92–0.96). High expression of PRC1 and DLGAP5 positively correlated with tumor recurrence and microvascular invasion, was an independent risk factor for poor overall survival. PRC1 and DLGAP5 were co-expressed in proliferative T cells over-expressing immunosuppressive markers PDCD1, CTLA4, HAVCR2, LAG3 and TIGIT based on single-cell RNA-sequencing datasets. Conclusions PRC1 and DLGAP5 significantly upregulated in HCC are associated with poor prognosis and show strong diagnostic potential. PRC1 or DLGAP5 combined with CD8 T cell markers may serve as predictive biomarkers for the efficacy of ICI combination therapy.