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A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti–PD-1 immunotherapy
Balamayoora Theivanthiran, … , Alisha Holtzhausen, Brent A. Hanks
Balamayoora Theivanthiran, … , Alisha Holtzhausen, Brent A. Hanks
Published February 4, 2020
Citation Information: J Clin Invest. 2020;130(5):2570-2586. https://doi.org/10.1172/JCI133055.
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Research Article Immunology Oncology Article has an altmetric score of 30

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

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Abstract

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.

Authors

Balamayoora Theivanthiran, Kathy S. Evans, Nicholas C. DeVito, Michael Plebanek, Michael Sturdivant, Luke P. Wachsmuth, April K.S. Salama, Yubin Kang, David Hsu, Justin M. Balko, Douglas B. Johnson, Mark Starr, Andrew B. Nixon, Alisha Holtzhausen, Brent A. Hanks

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Figure 6

Genetic and pharmacologic inhibition of NLRP3 suppresses PMN-MDSC recruitment and enhances the efficacy of anti–PD-1 Ab immunotherapy.

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Genetic and pharmacologic inhibition of NLRP3 suppresses PMN-MDSC recrui...
(A) Plasma HSP70 ELISA analysis following the growth of BRAFV600E PTEN–/– NTC or Nlrp3-silenced BRAFV600E PTEN–/– melanomas (n = 5). (B) qRT-PCR analysis of CXCR2-dependent chemokine expression in BRAFV600E PTEN–/– NTC and BRAFV600E PTEN–/– NLRP3KD melanomas (n = 3). (C) Flow cytometric analysis of CD8+ T cells in resected BRAFV600E PTEN–/– NTC and BRAFV600E PTEN–/– NLRP3KD melanomas (n = 5). Flow cytometric analysis of PMN-MDSCs in resected BRAFV600E PTEN–/– NTC and BRAFV600E PTEN–/– NLRP3KD melanomas (n = 5). (D) Tumor growth curve of BRAFV600E PTEN–/– NTC and BRAFV600E PTEN–/– NLRP3KD melanomas (n = 5). (E) Treatment of syngeneic BRAFV600E PTEN–/– melanomas with IgG isotype control Ab (200 μg i.p. every 3 days), NLRP3 inhibitor (10 μg MCC950 i.p. every 3 days), anti–PD-1 Ab (200 μg i.p. every 3 days), or NLRP3 inhibitor and anti–PD-1 Ab combination therapy (n = 8). (F) Representative flow cytometric dot plots of PMN-MDSCs and CD8+ T cells in resected BRAFV600E PTEN–/– melanomas following treatment with IgG isotype control Ab, NLRP3 inhibitor, anti–PD-1 Ab, or NLRP3 inhibitor and anti–PD-1 Ab combination therapy. Graphs show flow cytometric analysis of tumor-infiltrating PMN-MDSCs and CD44+CD8+ T cells. (G) Whole tumor tissue Western blot analysis for pro–caspase-1, caspase-1 p20, and Wnt5a following in vivo treatment with IgG isotype control, anti–PD-1 Ab, or combined anti–PD-1 Ab and NLRP3 inhibitor. Blots are representative of 2 independent experiments. (H) qRT-PCR analysis of Cxcl5 and granzyme B (Gzmb) expression in resected BRAFV600E PTEN–/– melanoma tissues (n = 5). *P < 0.05, **P < 0.005, and ***P < 0.0005, by Student’s t test (A–D) and 1-way ANOVA with Sidak’s post hoc multiple comparisons test (E, F, and H). See also Supplemental Figure 7.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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