Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression

F Cortesi, G Delfanti, Andrea Grilli, A Calcinotto, F Gorini, F Pucci, R Lucianò, M Grioni, Alessandra Recchia, F Benigni, A Briganti, A Salonia, Michele De Palma, S Bicciato, C Doglioni, M Bellone, G Casorati, P Dellabona

Research output: Contribution to journalArticle

Abstract

Heterotypic cellular and molecular interactions in the tumor microenvironment (TME) control cancer progression. Here, we show that CD1d-restricted invariant natural killer (iNKT) cells control prostate cancer (PCa) progression by sculpting the TME. In a mouse PCa model, iNKT cells restrained the pro-angiogenic and immunosuppressive capabilities of tumor-infiltrating immune cells by reducing pro-angiogenic TIE2+, M2-like macrophages (TEMs), and sustaining pro-inflammatory M1-like macrophages. iNKT cells directly contacted macrophages in the PCa stroma, and iNKT cell transfer into tumor-bearing mice abated TEMs, delaying tumor progression. iNKT cells modulated macrophages through the cooperative engagement of CD1d, Fas, and CD40, which promoted selective killing of M2-like and survival of M1-like macrophages. Human PCa aggressiveness associate with reduced intra-tumoral iNKT cells, increased TEMs, and expression of pro-angiogenic genes, underscoring the clinical significance of this crosstalk. Therefore, iNKT cells may control PCa through mechanisms involving differential macrophage modulation, which may be harnessed for therapeutically reprogramming the TME. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)3006-3020
Number of pages15
JournalCell Reports
Volume22
Issue number11
DOIs
Publication statusPublished - 2018

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Natural Killer T-Cells
Macrophages
Crosstalk
Tumors
Prostatic Neoplasms
Tumor Microenvironment
Neoplasms
Bearings (structural)
Molecular interactions
Immunosuppressive Agents
Natural Killer Cells
Genes
Modulation
Survival

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Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression. / Cortesi, F; Delfanti, G; Grilli, Andrea; Calcinotto, A; Gorini, F; Pucci, F; Lucianò, R; Grioni, M; Recchia, Alessandra; Benigni, F; Briganti, A; Salonia, A; De Palma, Michele; Bicciato, S; Doglioni, C; Bellone, M; Casorati, G; Dellabona, P.

In: Cell Reports, Vol. 22, No. 11, 2018, p. 3006-3020.

Research output: Contribution to journalArticle

Cortesi, F ; Delfanti, G ; Grilli, Andrea ; Calcinotto, A ; Gorini, F ; Pucci, F ; Lucianò, R ; Grioni, M ; Recchia, Alessandra ; Benigni, F ; Briganti, A ; Salonia, A ; De Palma, Michele ; Bicciato, S ; Doglioni, C ; Bellone, M ; Casorati, G ; Dellabona, P. / Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression. In: Cell Reports. 2018 ; Vol. 22, No. 11. pp. 3006-3020.
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AB - Heterotypic cellular and molecular interactions in the tumor microenvironment (TME) control cancer progression. Here, we show that CD1d-restricted invariant natural killer (iNKT) cells control prostate cancer (PCa) progression by sculpting the TME. In a mouse PCa model, iNKT cells restrained the pro-angiogenic and immunosuppressive capabilities of tumor-infiltrating immune cells by reducing pro-angiogenic TIE2+, M2-like macrophages (TEMs), and sustaining pro-inflammatory M1-like macrophages. iNKT cells directly contacted macrophages in the PCa stroma, and iNKT cell transfer into tumor-bearing mice abated TEMs, delaying tumor progression. iNKT cells modulated macrophages through the cooperative engagement of CD1d, Fas, and CD40, which promoted selective killing of M2-like and survival of M1-like macrophages. Human PCa aggressiveness associate with reduced intra-tumoral iNKT cells, increased TEMs, and expression of pro-angiogenic genes, underscoring the clinical significance of this crosstalk. Therefore, iNKT cells may control PCa through mechanisms involving differential macrophage modulation, which may be harnessed for therapeutically reprogramming the TME. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

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