NLRP3 Suppresses NK Cell-Mediated Responses to Carcinogen-Induced Tumors and Metastases

Cancer Res. 2012 Nov 15;72(22):5721-32. doi: 10.1158/0008-5472.CAN-12-0509. Epub 2012 Sep 17.

Abstract

The NLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response upon infectious insults or tissue injury and damage. However, the role of the NLRP3 inflammasome in natural killer (NK) cell-mediated control of tumor immunity is poorly understood. Here, we show in a model of chemical-induced carcinogenesis and a series of experimental and spontaneous metastases models that mice lacking NLRP3 display significantly reduced tumor burden than control wild-type (WT) mice. The suppression of spontaneous and experimental tumor metastases and methylcholanthrene (MCA)-induced sarcomas in mice deficient for NLRP3 was NK cell and IFN-γ-dependent. Focusing on the amenable B16F10 experimental lung metastases model, we determined that expression of NLRP3 in bone marrow-derived cells was necessary for optimal tumor metastasis. Tumor-driven expansion of CD11b(+)Gr-1(intermediate) (Gr-1(int)) myeloid cells within the lung tumor microenvironment of NLRP3(-/-) mice was coincident with increased lung infiltrating activated NK cells and an enhanced antimetastatic response. The CD11b(+)Gr-1(int) myeloid cells displayed a unique cell surface phenotype and were characterized by their elevated production of CCL5 and CXCL9 chemokines. Adoptive transfer of this population into WT mice enhanced NK cell numbers in, and suppression of, B16F10 lung metastases. Together, these data suggested that NLRP3 is an important suppressor of NK cell-mediated control of carcinogenesis and metastases and identify CD11b(+)Gr-1(int) myeloid cells that promote NK cell antimetastatic function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Animals
  • CD11b Antigen / immunology
  • Carrier Proteins / immunology*
  • Chemokine CCL5 / immunology
  • Chemokine CXCL9 / immunology
  • Fibrosarcoma / chemically induced
  • Fibrosarcoma / immunology
  • Fibrosarcoma / pathology
  • Inflammasomes / immunology
  • Killer Cells, Natural / immunology*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / secondary
  • Male
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / pathology
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / secondary
  • Methylcholanthrene
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Cells / immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neoplasm Metastasis
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / secondary
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / pathology

Substances

  • CD11b Antigen
  • Carrier Proteins
  • Ccl5 protein, mouse
  • Chemokine CCL5
  • Chemokine CXCL9
  • Cxcl9 protein, mouse
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Methylcholanthrene