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

• Published in: Nature communications Vol. 13; no. 1; pp. 6752 - 20
• Main Authors: Tiberti, Silvia, Catozzi, Carlotta, Croci, Ottavio, Ballerini, Mattia, Cagnina, Danilo, Soriani, Chiara, Scirgolea, Caterina, Gong, Zheng, He, Jiatai, Macandog, Angeli D., Nabinejad, Amir, Nava Lauson, Carina B., Quinte’, Arianna, Bertalot, Giovanni, Petz, Wanda L., Ravenda, Simona P., Licursi, Valerio, Paci, Paola, Rasponi, Marco, Rotta, Luca, Fazio, Nicola, Ren, Guangwen, Fumagalli-Romario, Uberto, Schaefer, Martin H., Campaner, Stefano, Lugli, Enrico, Nezi, Luigi, Manzo, Teresa
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/21; 13/31; 13/51; 13/62; 14; 14/1; 14/19; 49/39; 49/91; 59; 631/250/580; 631/67/1504/1885; 64; 64/60; Cancer; CD8 antigen; Colorectal cancer; Colorectal carcinoma; CXCL12 protein; E-cadherin; Effector cells; Epithelium; Humanities and Social Sciences; Immune system; Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; Memory cells; Metastases; Metastasis; Microenvironments; multidisciplinary; Neutrophils; Patients; Science; Science (multidisciplinary); SDF-1 protein; Solid tumors; Tumor-infiltrating lymphocytes; Tumors
• ISSN: 2041-1723; 2041-1723
• 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 EM ) 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 high CD8 + T EM 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. The tumor immune microenvironment is an important prognostic determinant in colorectal cancer (CRC). Here the authors show that tumor infiltrating neutrophils expressing high levels of CD15 interact with CD8 + T effector memory skewing them to produce GZMK, associated with tumor progression in CRC patients.