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:
Notes: Article -- Export Date: 2 August 2021 -- Source: Scopus
Altmetric
Citation Impact
MSK Authors
  1. Jedd D Wolchok
    859 Wolchok
  2. Taha Merghoub
    329 Merghoub
  3. Dmitriy Zamarin
    148 Zamarin
  4. Katherine S Panageas
    443 Panageas
  5. Cailian Liu
    54 Liu
  6. Jason S Lewis
    381 Lewis
  7. Sadna Budhu
    73 Budhu
  8. Matthew David Hellmann
    377 Hellmann
  9. Hong Zhong
    27 Zhong
  10. Charles Rudin
    356 Rudin
  11. Nisargbhai Sanjaykumar Shah
    20 Shah
  12. Inna   Khodos
    27 Khodos
  13. Sai Kiran   Sharma
    25 Sharma
  14. Joseph Minhow Chan
    27 Chan
  15. Viola   Allaj
    23 Allaj
  16. Marissa   Mattar
    44 Mattar
  17. Hira Abbas Rizvi
    105 Rizvi
  18. Sohrab Prakash Shah
    42 Shah
  19. Aditi Gupta
    14 Gupta
  20. Yonina Bykov
    11 Bykov
  21. Andrew Chow
    26 Chow
  22. Nicholas Ceglia
    7 Ceglia
  23. Triparna Sen
    44 Sen
  24. Justin Shaun Arnold Perry
    8 Perry
  25. Fathema Zannath Uddin
    17 Uddin
  26. Giulia Zago
    3 Zago
  27. Hongyu Shi
    5 Shi