Lea Spencer T, Chen Chao-Hsien, Wei Jun, William Ivana, Lopez Del Castillo Inés, Curran Michael A
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas.
Cancer Res Commun. 2025 Jun 1;5(6):960-972. doi: 10.1158/2767-9764.CRC-23-0189.
Glioblastoma (GBM) is the most common and deadly primary brain malignancy and is clinically refractory to immunotherapy. Active NLRP3 inflammasome signaling and IL-1β secretion have been observed in GBM, and NLRP3-driven myeloid-derived suppressor cell (MDSC) recruitment can mediate cancer immune evasion. Agonists of the cytosolic double-stranded DNA-sensing stimulator of IFN gene (STING) pathway can mediate proinflammatory conversion of cancer MDSCs; however, secretion of the NLRP3 products IL-1β and IL-18 has also been observed in certain myeloid populations following STING activation. In this study, we aimed to determine both the potential mechanistic synergy between STING and NLRP3 agonists, and the effects of this innate immune combination on the GBM tumor immune landscape. We find that STING activation does not prime pro-IL-1β expression for activated NLRP3 inflammasome secretion. In subcutaneous GL261 GBM, we show that NLRP3 activation expands the immunosuppressive myeloid stroma primarily via granulocytic MDSC recruitment and antagonizes the benefit of STING activation. In brain GL261, we find that NLRP3 activation expands granulocytic MDSCs but does not antagonize the therapeutic benefit of STING activation. Finally, we report that mesenchymal subtype GBM tumors have elevated neutrophil, IL-1β, and NLRP3 gene expression, a setting where our data suggest that NLRP3 activation could counteract STING agonists.
NLRP3 inflammasome signaling, which suppresses antitumor immunity in some cancers, has been observed in GBM tissues. NLRP3 activation in GBM induces granulocyte-dependent tumor immunosuppression and antagonizes the therapeutic efficacy of STING activation.
胶质母细胞瘤（GBM）是最常见且致命的原发性脑恶性肿瘤，临床上对免疫治疗具有耐药性。在GBM中已观察到活跃的NLRP3炎性小体信号传导和白细胞介素-1β（IL-1β）分泌，并且NLRP3驱动的髓源性抑制细胞（MDSC）募集可介导癌症免疫逃逸。细胞质双链DNA感应干扰素基因（STING）途径的激动剂可介导癌症MDSC的促炎转化；然而，在STING激活后的某些髓系细胞群中也观察到了NLRP3产物IL-1β和IL-18的分泌。在本研究中，我们旨在确定STING和NLRP3激动剂之间潜在的机制协同作用，以及这种先天免疫组合对GBM肿瘤免疫格局的影响。我们发现STING激活不会引发激活的NLRP3炎性小体分泌的前体IL-1β表达。在皮下GL261 GBM中，我们表明NLRP3激活主要通过粒细胞MDSC募集扩大免疫抑制性髓质基质，并拮抗STING激活的益处。在脑内GL261中，我们发现NLRP3激活扩大了粒细胞MDSC，但不会拮抗STING激活的治疗益处。最后，我们报告间充质亚型GBM肿瘤的中性粒细胞、IL-1β和NLRP3基因表达升高，在这种情况下，我们的数据表明NLRP3激活可能抵消STING激动剂的作用。
在GBM组织中已观察到NLRP3炎性小体信号传导，其在某些癌症中抑制抗肿瘤免疫。GBM中的NLRP3激活诱导粒细胞依赖性肿瘤免疫抑制，并拮抗STING激活的治疗效果。
