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

Silvia Tiberti, Carlotta Catozzi, Ottavio Croci, Mattia Ballerini, Danilo Cagnina, Chiara Soriani, Caterina Scirgolea, Zheng Gong, Jiatai He, Angeli D. Macandog, Amir Nabinejad, Carina B. Nava Lauson, Arianna Quinte’, Giovanni Bertalot, Wanda L. Petz, Simona P. Ravenda, Valerio Licursi, Paola Paci, Marco Rasponi, Luca Rotta, Nicola Fazio, Guangwen Ren, Uberto Fumagalli-Romario, Martin H. Schaefer, Stefano Campaner, Enrico Lugli, Luigi Nezi () and Teresa Manzo ()
Additional contact information
Silvia Tiberti: European Institute of Oncology- IRCCS
Carlotta Catozzi: European Institute of Oncology- IRCCS
Ottavio Croci: Fondazione Istituto Italiano di Tecnologia (IIT)
Mattia Ballerini: European Institute of Oncology- IRCCS
Danilo Cagnina: European Institute of Oncology- IRCCS
Chiara Soriani: European Institute of Oncology- IRCCS
Caterina Scirgolea: IRCCS- Humanitas Research Hospital-
Zheng Gong: The Jackson Laboratory
Jiatai He: The Jackson Laboratory
Angeli D. Macandog: European Institute of Oncology- IRCCS
Amir Nabinejad: European Institute of Oncology- IRCCS
Carina B. Nava Lauson: European Institute of Oncology- IRCCS
Arianna Quinte’: European Institute of Oncology- IRCCS
Giovanni Bertalot: APSS Trento Hospital & Health Care
Wanda L. Petz: European Institute of Oncology-IRCCS
Simona P. Ravenda: European Institute of Oncology-IRCCS
Valerio Licursi: National Research Council (CNR) of Italy
Paola Paci: Sapienza - University of Rome
Marco Rasponi: Information and Bioengineering, Politecnico di Milano
Luca Rotta: European Institute of Oncology- IRCCS
Nicola Fazio: European Institute of Oncology-IRCCS
Guangwen Ren: The Jackson Laboratory
Uberto Fumagalli-Romario: European Institute of Oncology-IRCCS
Martin H. Schaefer: European Institute of Oncology- IRCCS
Stefano Campaner: Fondazione Istituto Italiano di Tecnologia (IIT)
Enrico Lugli: IRCCS- Humanitas Research Hospital-
Luigi Nezi: European Institute of Oncology- IRCCS
Teresa Manzo: European Institute of Oncology- IRCCS

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34467-3

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