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

• Published in: Cell reports (Cambridge) Vol. 22; no. 11; pp. 3006 - 3020
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.03.2018; Elsevier
• Subjects: angiogenesis; Animals; CD1d; CD40; CD40 Antigens - metabolism; Disease Progression; Fas; Humans; immunotherapy; iNKT cells; macrophage; Macrophages - metabolism; Male; Mice; Natural Killer T-Cells - immunology; prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; tumor microenvironment; prostate cancer; CD40; iNKT cells; angiogenesis; immunotherapy; macrophage; Fas; CD1d; tumor microenvironment
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.02.058

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. [Display omitted] •iNKT cells remodel the tumor microenvironment of mouse prostate cancer•iNKT cells restrict pro-angiogenic TEMs and sustain pro-inflammatory TAMs•iNKT cells differentially modulate TAMs by cooperative CD1d, CD40, and Fas engagement•Aggressive human prostate cancers contain high TEMs and low iNKT cells 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.