Lighting a Fire: Gasdermin-Mediated Pyroptosis Remodels the Glioma Microenvironment and Promotes Immune Checkpoint Blockade Response

Abstract

Pyroptosis is a proinflammatory programmed cell death pathway mediated by gasdermins. Exploring the role of pyroptosis can provide new insights into tumor malignancy. The most recent studies on pyroptosis have focused on tumor cells. However, the effects of pyroptosis on the tumor microenvironment (TME), immunotherapeutic responses, and efficacy have been neglected, especially in case of glioma. In this study, four independent glioma cohorts comprising 1,339 samples and a pan-cancer cohort comprising 10,535 tumor samples were analyzed. The relationships among pyroptosis status, prognosis, microenvironment cellular components, and clinical and biological phenotypes were investigated through the identification of pyroptosis subtypes, construction of a gasdermin-related prognostic index (GPI), and evaluation of immunological characteristics in glioma. The Genomics of Drug Sensitivity in Cancer database and “pRRophetic” package in R were used to estimate temozolomide (TMZ) sensitivity. The “Submap” package and external immunotherapy cohorts were used to investigate and confirm the role of GPI in response to and efficacy of immunotherapy in glioma. Finally, potential small-molecule compounds related to GPI were identified using the connectivity map database and mode-of-action analysis. We identified three different pyroptosis subtypes: cluster 1 (C1) characterized by a higher GPI, while cluster 2 (C2) and cluster 3 (C3) characterized by a lower GPI. The high GPI of C1 was associated with glioma progression and worse prognoses, whereas the low GPI of subtype C2 and C3 was associated with better prognoses. However, patients with high GPIs were found to be more sensitive to TMZ and immune checkpoint blockade than those with low GPIs. Furthermore, gasdermin D may be a principal potential biomarker and play key roles in pyroptosis-inducible therapy combined with immunotherapy in glioma. This study provides a clinical, biological, and molecular landscape of pyroptosis and suggests that pyroptosis of glioma cells may perform the dual function of promoting both tumorigenesis and antitumor immunity.

Gasdermins: a dual role in pyroptosis and tumor immunity

“…As the most common malignant tumor in the central nervous system, glioma has a very poor prognosis ( 126 ). Pyroptosis induced by GSDMD and NLRC4 in high-grade gliomas can promote the progression of gliomas and enhance the sensitivity of these tumors to immune checkpoint therapy by recruiting immune cells ( 127 ). The inflammatory immune microenvironment induced by pyroptosis can promote the invasion and proliferation of glioma stem cells and is also related to the infiltration of M2 pheno-type bone marrow-derived macrophages (BMDMs) ( 72 , 128 ).…”

“…The inflammatory immune microenvironment induced by pyroptosis can promote the invasion and proliferation of glioma stem cells and is also related to the infiltration of M2 pheno-type bone marrow-derived macrophages (BMDMs) ( 72 , 128 ). In the future, it is necessary to construct a GSDMD-deficient mouse model to probe the effects of pyroptosis as a drug target on gliogenesis and the tumor immune microenvironment ( 72 , 127 ).…”

Dual-Responsive Nanomedicine Activates Programmed Antitumor Immunity through Targeting Lymphatic System

“…Among various therapeutic modalities, pyroptosis as a type of inflammatory programmed cell death has the powerful capacity to induce robust ICD, which is executed by the proteolytic cleavage of gasdermin (GSDM) family proteins. , Under the cleavage of specific caspases and proteases, GSDM proteins produce a necrotic N-terminal domain capable of plasma membrane perforation, leading to a swift plasma membrane rupture and the release of DAMPs and proinflammatory cytokines . It is documented that pyroptosis as a recently identified form of ICD has the potential to maximize the ICB response rate for a robust and durable antitumor response in both preclinical tumor models and clinical cancer patients. − For instance, the Lieberman group found that granzyme B (GZMB) secreted by tumor-infiltrating natural killer (NK) and CD8 + T lymphocytes could cleave gasdermin E (GSDME) to induce pyroptosis of cancer cells, resulting in enhanced antitumor immunity . However, the GSDM expression was downregulated in most cancer types, thus limiting the efficacy of triggering pyroptosis for antitumor immunity .…”

Identification of cuproptosis-related subtypes and the development of a prognostic model in glioma

“…In this study, we used naming rules of databases and classified LGG as grade 2 and 3 glioma, HGG as grade 4 glioma. A variety of cell death modes have been confirmed to be present in glioma and participate in the tumor microenvironment (TME) (Cai et al, 2022;Liu et al, 2022). Cuproptosis may play a role in glioma development and progression of glioma.…”