Type I IFN, Ly6C⁺ cells, and Phagocytes Support Suppression of Peritoneal Carcinomatosis Elicited by a TLR and CLR Agonist Combination.

ABSTRACT: Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Our previous study demonstrated a Toll-like receptor and C-type lectin receptor agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development following TA3-Ha and EL4 challenge through a mechanism dependent on B-1a cell-produced natural IgM and complement. In this study, we investigated additional players in the MPL/TDCM-elicited response. MPL/TDCM treatment rapidly increased type I IFN levels in the peritoneal cavity along with myeloid cell numbers, including macrophages and Ly6C^hi monocytes. Type I IFN receptor (IFNAR1^-/-) mice produced tumor-reactive IgM following MPL/TDCM treatment, but failed to recruit Ly6C⁺ monocytes and were not afforded protection during tumor challenges. Clodronate liposome depletion of phagocytic cells, as well as targeted depletion of Ly6C⁺ cells, also ablated MPL/TDCM-induced protection. Cytotoxic mediators known to be produced by these cells were required for effects. TNFα was required for effective TA3-Ha killing and nitric oxide was required for EL4 killing. Collectively, these data reveal a model whereby MPL/TDCM-elicited antitumor effects strongly depend on innate cell responses, with B-1a cell-produced tumor-reactive IgM and complement pairing with myeloid cell-produced cytotoxic mediators to effectively eradicate tumors in the peritoneal cavity.

SUBMITTER: Dyevoich AM 

PROVIDER: S-EPMC7770648 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature