Pharmaceuticals (May 2022)

Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers

  • Isak W. Tengesdal,
  • Suzhao Li,
  • Nicholas E. Powers,
  • Makenna May,
  • Charles P. Neff,
  • Leo A. B. Joosten,
  • Carlo Marchetti,
  • Charles A. Dinarello

DOI
https://doi.org/10.3390/ph15050574
Journal volume & issue
Vol. 15, no. 5
p. 574

Abstract

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Tumor-associated inflammation leads to dysregulated cytokine production that promotes tumor immune evasion and anti-tumor immunity dysfunction. In advanced stage breast cancer, the proinflammatory cytokine IL-1β is overexpressed due to large proportions of activated myeloid cells in the tumor microenvironment (TME). Here, we demonstrate the role of the host nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing 3 (NLRP3) inflammasome in metastatic breast cancer. In vitro, we show that stimulation of THP-1 cells with conditioned media collected from MDA-MB-468 cells induced NLRP3 activation and increased Pdcd1l1 expression. In vivo, mice deficient in NLRP3 orthotopically implanted with metastatic breast cancer cell line (E0771) showed significant reduction in tumor growth (p p ® reduced expression of Pdcd1l1 (p Casp1 (p Il1b (p ® showed reduced infiltration of myeloid-derived suppressor cells (MDSCs) (p + T cells (p p p < 0.05). These data define NLRP3 activation as a key driver of immune suppression in metastatic breast cancers. Furthermore, this study suggests NLRP3 as a valid target to increase efficacy of immunotherapy with checkpoint inhibitor in metastatic breast cancers.

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