GZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in non-metastatic colorectal tumors and predict poor clinical outcome

Author:

Tiberti Silvia,Catozzi CarlottaORCID,Croci Ottavio,Ballerini Mattia,Cagnina DaniloORCID,Soriani ChiaraORCID,Scirgolea CaterinaORCID,Gong Zheng,He Jiatai,Macandog Angeli D.,Nabinejad AmirORCID,Nava Lauson Carina B.,Quinte’ Arianna,Bertalot Giovanni,Petz Wanda L.,Ravenda Simona P.,Licursi ValerioORCID,Paci PaolaORCID,Rasponi MarcoORCID,Rotta LucaORCID,Fazio Nicola,Ren GuangwenORCID,Fumagalli-Romario UbertoORCID,Schaefer Martin H.ORCID,Campaner Stefano,Lugli EnricoORCID,Nezi LuigiORCID,Manzo TeresaORCID

Abstract

AbstractCD8+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 GZMKhighCD8+TEMin 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.

Funder

Associazione Italiana per la Ricerca sul Cancro

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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