Inflammasomes - a driver of sexual dimorphism to glioma therapies

Duke University, Durham NC

Investigators

Abstract

ABSTRACT Malignant gliomas remain lethal with available therapies, including immune checkpoint blockade. Tumor cells and glioma-associated microglia/macrophages (GAMMs) collectively activate inflammatory responses in the tumor microenvironment (TME), leading to immune suppression, therapy resistance, tumor progression, and relapse. Hence, targeting the protumorigenic TME inflammation is an attractive approach against gliomas. TME inflammation can be induced by inflammasomes, cytosolic innate immune protein complexes that induce cytokine secretion. The NLRP3 inflammasome is expressed in multiple immune cells, and we have identified a population of NLRP3+IL- + proinflammatory macrophages in gliomas. Intriguingly, we found that (1) NLRP3+IL- + GAMMs are increased in both normal and glioma-bearing females, (2) NLRP3-responsive inflammatory genes are enriched in the mesenchymal glioblastoma subtype, (3) high NLRP3 levels are associated with a poor prognosis in female mesenchymal glioblastoma patients, and (4) inflammasome and inflammatory proteins are higher in gliomas from female mice. Our data is consistent with the known inflammatory propensity of females and the presence of key immune regulatory genes on the X chromosome. To determine whether NLRP3 inhibition would overcome inflammation-induced immune suppression and potentiate antitumor immune therapies, we treated male and female glioma-bearing mice with an EGFR targeting antibody toxin conjugate (ATC) and either pharmacological inhibition or genetic deletion of NLRP3. ATC + NLRP3 inhibition/deletion significantly prolonged survival in female but not male mice. In addition, estrogen receptor signaling inhibition decreased NLRP3 and Caspase-1 levels in gliomas during ATC or radiation therapy, indicating a role for sex hormones in NLRP3 regulation. Hence, we hypothesize that NLRP3-induced inflammatory responses promote immune suppression and dampen therapy-induced antitumor responses, specifically in females. Herein, we will 1) Determine whether NLRP3+IL- + GAMMs are primary regulators of sex-dependent ATC therapy response, 2) Determine whether sex hormones vs. sex chromosomes regulate NLRP3 and sex-dependent ATC antitumor response, and 3) Determine whether NLRP3 signaling regulates antitumor responses to radiotherapy in a sex- dependent manner. 1