Synapse - Tim-4(+) cavity-resident macrophages impair anti-tumor CD8(+) T cell immunity

Tim-4(+) cavity-resident macrophages impair anti-tumor CD8(+) T cell immunity Journal Article

Authors:	Chow, A.; Schad, S.; Green, M. D.; Hellmann, M. D.; Allaj, V.; Ceglia, N.; Zago, G.; Shah, N. S.; Sharma, S. K.; Mattar, M.; Chan, J.; Rizvi, H.; Zhong, H.; Liu, C.; Bykov, Y.; Zamarin, D.; Shi, H.; Budhu, S.; Wohlhieter, C.; Uddin, F.; Gupta, A.; Khodos, I.; Waninger, J. J.; Qin, A.; Markowitz, G. J.; Mittal, V.; Balachandran, V.; Durham, J. N.; Le, D. T.; Zou, W.; Shah, S. P.; McPherson, A.; Panageas, K.; Lewis, J. S.; Perry, J. S. A.; de Stanchina, E.; Sen, T.; Poirier, J. T.; Wolchok, J. D.; Rudin, C. M.; Merghoub, T.
Article Title:	Tim-4(+) cavity-resident macrophages impair anti-tumor CD8(+) T cell immunity
Abstract:	Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8+ T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer. We mechanistically demonstrate that viable and cytotoxic anti-tumor CD8+ T cells upregulate PS and this renders them susceptible to sequestration away from tumor targets and proliferation suppression by Tim-4+ macrophages. Tim-4 blockade abrogates this sequestration and proliferation suppression and enhances anti-tumor efficacy in models of anti-PD-1 therapy and adoptive T cell therapy in mice. Thus, Tim-4+ cavity-resident macrophages limit the efficacy of immunotherapies in these microenvironments. © 2021
Keywords:	immunotherapy; phosphatidylserine; immune checkpoint blockade; cd8+ t cells; sequestration; scrna-seq; tim-4; cavity-resident macrophages; peritoneal macrophages; pleural macrophages
Journal Title:	Cancer Cell
Volume:	39
Issue:	7
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2021-07-12
Start Page:	973
End Page:	988.e9
Language:	English
DOI:	10.1016/j.ccell.2021.05.006
PUBMED:	34115989
PROVIDER:	scopus
PMCID:	PMC9115604
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85109428361&doi=10.1016%2fj.ccell.2021.05.006&partnerID=40&md5=4d89668faf705e15ae717586d72ef819
Notes:	Article -- Export Date: 2 August 2021 -- Source: Scopus