Department of Experimental Oncology, European Institute of Oncology- IRCCS, Milano, Italy.
Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), Milano, Italy.
Nat Commun. 2022 Nov 8;13(1):6752. doi: 10.1038/s41467-022-34467-3.
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 (T) 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 GZMK CD8 T 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.
CD8 T 细胞是实体瘤(包括结直肠癌)的一个主要预后决定因素。然而,对于不同免疫细胞之间的相互作用如何影响临床结果,我们仍处于起步阶段。在这里,我们描述了表达高水平 CD15 的肿瘤浸润中性粒细胞与 CD8 效应记忆 T 细胞(T)的相互作用与肿瘤进展相关。从机制上讲,基质细胞衍生因子-1(CXCL12/SDF-1)促进中性粒细胞在肿瘤内的保留,增加与 CD8 T 细胞的串扰。由于与中性粒细胞的接触介导的相互作用,CD8 T 细胞偏向于产生高水平的 GZMK,这反过来又降低了肠道上皮细胞上的 E-钙粘蛋白,并有利于肿瘤进展。总的来说,我们的结果强调了非转移性 CRC 肿瘤中 GZMK CD8 T 的出现是由与中性粒细胞相互作用驱动的一个标志,这可能可以实现当前的患者分层,并成为新的治疗方法的靶点。
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