Skip to main content

A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.

Publication ,  Journal Article
Theivanthiran, B; Evans, KS; DeVito, NC; Plebanek, M; Sturdivant, M; Wachsmuth, LP; Salama, AK; Kang, Y; Hsu, D; Balko, JM; Johnson, DB ...
Published in: J Clin Invest
May 1, 2020

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

May 1, 2020

Volume

130

Issue

5

Start / End Page

2570 / 2586

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Tumor Escape
  • Translational Research, Biomedical
  • Signal Transduction
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Myeloid-Derived Suppressor Cells
  • Models, Immunological
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Theivanthiran, B., Evans, K. S., DeVito, N. C., Plebanek, M., Sturdivant, M., Wachsmuth, L. P., … Hanks, B. A. (2020). A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy. J Clin Invest, 130(5), 2570–2586. https://doi.org/10.1172/JCI133055
Theivanthiran, Balamayoora, Kathy S. Evans, Nicholas C. DeVito, Michael Plebanek, Michael Sturdivant, Luke P. Wachsmuth, April Ks Salama, et al. “A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.J Clin Invest 130, no. 5 (May 1, 2020): 2570–86. https://doi.org/10.1172/JCI133055.
Theivanthiran B, Evans KS, DeVito NC, Plebanek M, Sturdivant M, Wachsmuth LP, et al. A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy. J Clin Invest. 2020 May 1;130(5):2570–86.
Theivanthiran, Balamayoora, et al. “A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.J Clin Invest, vol. 130, no. 5, May 2020, pp. 2570–86. Pubmed, doi:10.1172/JCI133055.
Theivanthiran B, Evans KS, DeVito NC, Plebanek M, Sturdivant M, Wachsmuth LP, Salama AK, Kang Y, Hsu D, Balko JM, Johnson DB, Starr M, Nixon AB, Holtzhausen A, Hanks BA. A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy. J Clin Invest. 2020 May 1;130(5):2570–2586.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

May 1, 2020

Volume

130

Issue

5

Start / End Page

2570 / 2586

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Tumor Escape
  • Translational Research, Biomedical
  • Signal Transduction
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Myeloid-Derived Suppressor Cells
  • Models, Immunological
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice