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

Filippo Cortesi, Gloria Delfanti, Andrea Grilli, Arianna Calcinotto, Francesca Gorini, Ferdinando Pucci, Roberta Lucianò, Matteo Grioni, Alessandra Recchia, Fabio Benigni, Alberto Briganti, Andrea Salonia, Michele De Palma, Silvio Bicciato, Claudio Doglioni, Matteo Bellone, Giulia Casorati, Paolo Dellabona

Research output: Contribution to journalArticle

10 Citations (Scopus)

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. Cortesi et al. provide evidence that iNKT cells contribute to cancer immune surveillance. Due to differential tuning of tumor-associated macrophage populations, iNKT cells remodel the microenvironment of prostate cancer, enforcing a tumor-opposing state that controls tumor progression.

Original languageEnglish (US)
Pages (from-to)3006-3020
Number of pages15
JournalCell Reports
Volume22
Issue number11
DOIs
StatePublished - Mar 13 2018
Externally publishedYes

Fingerprint

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

Keywords

  • angiogenesis
  • CD1d
  • CD40
  • Fas
  • immunotherapy
  • iNKT cells
  • macrophage
  • prostate cancer
  • tumor microenvironment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression. / Cortesi, Filippo; Delfanti, Gloria; Grilli, Andrea; Calcinotto, Arianna; Gorini, Francesca; Pucci, Ferdinando; Lucianò, Roberta; Grioni, Matteo; Recchia, Alessandra; Benigni, Fabio; Briganti, Alberto; Salonia, Andrea; De Palma, Michele; Bicciato, Silvio; Doglioni, Claudio; Bellone, Matteo; Casorati, Giulia; Dellabona, Paolo.

In: Cell Reports, Vol. 22, No. 11, 13.03.2018, p. 3006-3020.

Research output: Contribution to journalArticle

Cortesi, F, Delfanti, G, Grilli, A, Calcinotto, A, Gorini, F, Pucci, F, Lucianò, R, Grioni, M, Recchia, A, Benigni, F, Briganti, A, Salonia, A, De Palma, M, Bicciato, S, Doglioni, C, Bellone, M, Casorati, G & Dellabona, P 2018, 'Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression', Cell Reports, vol. 22, no. 11, pp. 3006-3020. https://doi.org/10.1016/j.celrep.2018.02.058
Cortesi, Filippo ; Delfanti, Gloria ; Grilli, Andrea ; Calcinotto, Arianna ; Gorini, Francesca ; Pucci, Ferdinando ; Lucianò, Roberta ; Grioni, Matteo ; Recchia, Alessandra ; Benigni, Fabio ; Briganti, Alberto ; Salonia, Andrea ; De Palma, Michele ; Bicciato, Silvio ; Doglioni, Claudio ; Bellone, Matteo ; Casorati, Giulia ; Dellabona, Paolo. / 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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AU - Grilli, Andrea

AU - Calcinotto, Arianna

AU - Gorini, Francesca

AU - Pucci, Ferdinando

AU - Lucianò, Roberta

AU - Grioni, Matteo

AU - Recchia, Alessandra

AU - Benigni, Fabio

AU - Briganti, Alberto

AU - Salonia, Andrea

AU - De Palma, Michele

AU - Bicciato, Silvio

AU - Doglioni, Claudio

AU - Bellone, Matteo

AU - Casorati, Giulia

AU - Dellabona, Paolo

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N2 - 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. Cortesi et al. provide evidence that iNKT cells contribute to cancer immune surveillance. Due to differential tuning of tumor-associated macrophage populations, iNKT cells remodel the microenvironment of prostate cancer, enforcing a tumor-opposing state that controls tumor progression.

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. Cortesi et al. provide evidence that iNKT cells contribute to cancer immune surveillance. Due to differential tuning of tumor-associated macrophage populations, iNKT cells remodel the microenvironment of prostate cancer, enforcing a tumor-opposing state that controls tumor progression.

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