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Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1

Balamayooran Theivanthiran1, Nagendra Yarla1, Tarek Haykal1

  • 1Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27710, USA.

Science Translational Medicine
|November 23, 2022
PubMed

Insights

The NLRP3 inflammasome-HSP70 pathway drives cancer hyperprogression by promoting PMN-MDSC lung accumulation. Inhibiting NLRP3 and HSP70 suppressed metastasis and improved outcomes in preclinical models.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome-heat shock protein 70 (HSP70) axis contributes to adaptive resistance against anti-programmed cell death protein 1 (PD-1) immunotherapy.
  • This axis recruits granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment, promoting resistance.

Purpose of the Study:

  • To investigate the role of the tumor NLRP3-HSP70 axis in driving PMN-MDSC accumulation in distant lung tissues.
  • To elucidate the mechanisms by which this axis establishes a premetastatic niche supporting disease hyperprogression during anti-PD-1 immunotherapy.
  • To identify potential therapeutic targets and biomarkers for managing melanoma patients undergoing anti-PD-1 therapy.

Main Methods:

  • Investigated the tumor NLRP3-HSP70 axis and its effect on PMN-MDSC accumulation in lung tissues.
  • Utilized genetic and pharmacologic inhibition of NLRP3 and HSP70 in preclinical models of melanoma and breast cancer.
  • Analyzed plasma HSP70 concentrations and NLRP3 signaling activity in tumor tissues from stage IV melanoma patients.

Main Results:

  • The tumor NLRP3-HSP70 axis drives PMN-MDSC accumulation in lung tissues via lung epithelial Toll-like receptor 4 (TLR4) signaling.
  • This signaling cascade involves Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), promoting myeloid granulopoiesis and PMN-MDSC recruitment.
  • Anti-PD-1 immunotherapy exacerbated this pathway, leading to disease progression, particularly with Nlrp3 amplification. Inhibition of NLRP3 and HSP70 suppressed lung PMN-MDSC accumulation and metastatic progression.

Conclusions:

  • The tumor NLRP3-HSP70 axis establishes a premetastatic niche in the lungs, driving PMN-MDSC accumulation and disease hyperprogression in response to anti-PD-1 immunotherapy.
  • Elevated plasma HSP70 and tumor NLRP3 signaling correlate with disease hyperprogression and poor survival in melanoma patients treated with anti-PD-1 therapy.
  • NLRP3 and HSP70 represent promising therapeutic targets, and plasma HSP70 a potential biomarker for improving anti-PD-1 immunotherapy outcomes in melanoma.

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