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

被引:48
作者
Tiberti, Silvia [1 ]
Catozzi, Carlotta [1 ]
Croci, Ottavio [2 ]
Ballerini, Mattia [1 ]
Cagnina, Danilo [1 ]
Soriani, Chiara [1 ]
Scirgolea, Caterina [3 ]
Gong, Zheng [4 ]
He, Jiatai [4 ,5 ]
Macandog, Angeli D. [1 ]
Nabinejad, Amir [1 ]
Lauson, Carina B. Nava [1 ]
Quinte, Arianna [1 ]
Bertalot, Giovanni [6 ]
Petz, Wanda L. [7 ]
Ravenda, Simona P. [8 ]
Licursi, Valerio [9 ]
Paci, Paola [10 ]
Rasponi, Marco [11 ]
Rotta, Luca [1 ]
Fazio, Nicola [7 ]
Ren, Guangwen [4 ]
Fumagalli-Romario, Uberto [7 ]
Schaefer, Martin H. [1 ]
Campaner, Stefano [2 ]
Lugli, Enrico [3 ]
Nezi, Luigi [1 ]
Manzo, Teresa [1 ]
机构
[1] European Inst Oncol IRCCS, Dept Expt Oncol, Milan, Italy
[2] Fdn Ist Italiano Tecnol IIT, Ctr Genom Sci IIT, CGS SEMM Ist Italiano Tecnol, European Sch Mol Med, Milan, Italy
[3] IRCCS Humanitas Res Hosp, Lab Translat Immunol, Milan, Italy
[4] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA
[5] Univ Maine, Dept Mol & Biomed Sci, Orono, ME 04469 USA
[6] APSS Trento Hosp & Hlth Care, Dept Pathol, Trento, Italy
[7] European Inst Oncol IRCCS, Digest Surg Div, Milan, Italy
[8] European Inst Oncol IRCCS, Div Gastrointestinal Med Oncol & Neuroendocrine T, Milan, Italy
[9] Natl Res Council CNR Italy, Inst Mol Biol & Pathol IBPM, Rome, Italy
[10] Sapienza Univ Rome, Dept Comp Control & Management Engn, Rome, Italy
[11] Politecn Milan, Dept Elect Informat & Bioengn, Milan, Italy
关键词
PROGNOSTIC-FACTOR; SUPPRESSOR-CELLS; DENDRITIC CELLS; G-CSF; CANCER; LUNG; ACTIVATION; MIGRATION; GROWTH; INFLAMMATION;
D O I
10.1038/s41467-022-34467-3
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. 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.
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页数:20
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共 113 条
[1]   'Educated' dendritic cells act as messengers from memory to naive T helper cells [J].
Alpan, O ;
Bachelder, E ;
Isil, E ;
Arnheiter, H ;
Matzinger, P .
NATURE IMMUNOLOGY, 2004, 5 (06) :615-622
[2]   Co-option of Neutrophil Fates by Tissue Environments [J].
Ballesteros, Ivan ;
Rubio-Ponce, Andrea ;
Genua, Marco ;
Lusito, Eleonora ;
Kwok, Immanuel ;
Fernandez-Calvo, Gabriel ;
Khoyratty, Tariq E. ;
van Grinsven, Erinke ;
Gonzalez-Hernandez, Sara ;
Angel Nicolas-Avila, Jose ;
Vicanolo, Tommaso ;
Maccataio, Antonio ;
Benguria, Alberto ;
Li, Jackson LiangYao ;
Adrover, Jose M. ;
Aroca-Crevillen, Alejandra ;
Quintana, Juan A. ;
Martin-Salamanca, Sandra ;
Mayo, Francisco ;
Ascher, Stefanie ;
Barbiera, Giulia ;
Soehnlein, Oliver ;
Gunzer, Matthias ;
Ginhoux, Florent ;
Sanchez-Cabo, Fatima ;
Nistal-Villan, Estanislao ;
Schulz, Christian ;
Dopazo, Ana ;
Reinhardt, Christoph ;
Udalova, Irina A. ;
Ng, Lai Guan ;
Ostuni, Renato ;
Hidalgo, Andres .
CELL, 2020, 183 (05) :1282-+
[3]   QuPath: Open source software for digital pathology image analysis [J].
Bankhead, Peter ;
Loughrey, Maurice B. ;
Fernandez, Jose A. ;
Dombrowski, Yvonne ;
Mcart, Darragh G. ;
Dunne, Philip D. ;
McQuaid, Stephen ;
Gray, Ronan T. ;
Murray, Liam J. ;
Coleman, Helen G. ;
James, Jacqueline A. ;
Salto-Tellez, Manuel ;
Hamilton, Peter W. .
SCIENTIFIC REPORTS, 2017, 7
[4]   Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells [J].
Bengsch, Bertram ;
Ohtani, Takuya ;
Khan, Omar ;
Setty, Manu ;
Manne, Sasikanth ;
O'Brien, Shaun ;
Gherardini, Pier Federico ;
Herati, Ramin Sedaghat ;
Huang, Alexander C. ;
Chang, Kyong-Mi ;
Newell, Evan W. ;
Bovenschen, Niels ;
Pe'er, Dana ;
Albelda, Steven M. ;
Wherry, E. John .
IMMUNITY, 2018, 48 (05) :1029-+
[5]   High levels of tumor-associated neutrophils are associated with improved overall survival in patients with stage II colorectal cancer [J].
Berry, Ryan S. ;
Xiong, Meng-Jun ;
Greenbaum, Alissa ;
Mortaji, Parisa ;
Nofchissey, Robert A. ;
Schultz, Fred ;
Martinez, Cathleen ;
Luo, Li ;
Morris, Katherine T. ;
Hanson, Joshua A. .
PLOS ONE, 2017, 12 (12)
[6]   Understanding the tumor immune microenvironment (TIME) for effective therapy [J].
Binnewies, Mikhail ;
Roberts, Edward W. ;
Kersten, Kelly ;
Chan, Vincent ;
Fearon, Douglas F. ;
Merad, Miriam ;
Coussens, Lisa M. ;
Gabrilovich, Dmitry I. ;
Ostrand-Rosenberg, Suzanne ;
Hedrick, Catherine C. ;
Vonderheide, Robert H. ;
Pittet, Mikael J. ;
Jain, Rakesh K. ;
Zou, Weiping ;
Howcroft, T. Kevin ;
Woodhouse, Elisa C. ;
Weinberg, Robert A. ;
Krummel, Matthew F. .
NATURE MEDICINE, 2018, 24 (05) :541-550
[7]   Durable and controlled depletion of neutrophils in mice [J].
Boivin, Gael ;
Faget, Julien ;
Ancey, Pierre-Benoit ;
Gkasti, Aspasia ;
Mussard, Julie ;
Engblom, Camilla ;
Pfirschke, Christina ;
Contat, Caroline ;
Pascual, Justine ;
Vazquez, Jessica ;
Bendriss-Vermare, Nathalie ;
Caux, Christophe ;
Vozenin, Marie-Catherine ;
Pittet, Mikael J. ;
Gunzer, Matthias ;
Meylan, Etienne .
NATURE COMMUNICATIONS, 2020, 11 (01)
[8]   Intracellular and Extracellular Roles of Granzyme K [J].
Bouwman, Annemieke C. ;
van Daalen, Kim R. ;
Crnko, Sandra ;
ten Broeke, Toine ;
Bovenschen, Niels .
FRONTIERS IN IMMUNOLOGY, 2021, 12
[9]   Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards [J].
Bronte, Vincenzo ;
Brandau, Sven ;
Chen, Shu-Hsia ;
Colombo, Mario P. ;
Frey, Alan B. ;
Greten, Tim F. ;
Mandruzzato, Susanna ;
Murray, Peter J. ;
Ochoa, Augusto ;
Ostrand-Rosenberg, Suzanne ;
Rodriguez, Paulo C. ;
Sica, Antonio ;
Umansky, Viktor ;
Vonderheide, Robert H. ;
Gabrilovich, Dmitry I. .
NATURE COMMUNICATIONS, 2016, 7
[10]   Development, application and computational analysis of high-dimensional fluorescent antibody panels for single-cell flow cytometry [J].
Brummelman, Jolanda ;
Haftmann, Claudia ;
Nunez, Nicolas Gonzalo ;
Alvisi, Giorgia ;
Mazza, Emilia M. C. ;
Becher, Burkhard ;
Lugli, Enrico .
NATURE PROTOCOLS, 2019, 14 (07) :1946-1969