Sunday, May 18, 2025
5/18/2025
Cancer cell-intrinsic mitochondrial stress responses influence protective immunity - Epithelial ovarian cancer remains the most lethal gynecological malignancy in the United States, where the 5-year overall survival rate for patients with high-grade serous ovarian cancer (HGSOC) remains dismal at 34%. While the infiltration of T cells into ovarian tumor islets is clearly associated with prolonged survival in patients with ovarian cancer, recent advances in antitumor immunotherapeutic approaches rarely induce objective responses in these women. These outcomes reflect an incomplete understanding of the unique immunobiology of the ovarian tumor microenvironment (TME). Emerging evidence from our laboratory indicates that cancer cell-intrinsic dysfunction of mitochondrial stress response dramatically impairs the progression of ovarian cancer through provoking elevated antitumor immune responses. Mitochondrial fidelity is tightly linked to overall cellular homeostasis. The hostile nature of the ovarian TME, where cells encounter conditions of hypoxia, nutrient deprivation, and elevated oxidative stress, drive mitochondrial dysfunction. Such mitochondrial stress triggers adaptive responses to restore mitochondrial homeostasis, which facilitates malignant progression. Further understanding the cellular response to mitochondrial stress in ovarian cancer may be particularly important, as our laboratory has identified a germline encoded nonsynonymous single nucleotide polymorphism in the gene BLTP3A (found in ~18% of the population and predicted to generate a loss-of-function phenotype) that is associated with dramatically improved survival for high-grade serous ovarian cancer (HGSOC) patients. While the role BLTP3A in cancer remains elusive, preliminary research by our laboratory has revealed that BLTP3A promotes mitochondrial homeostasis through facilitating mitophagy in HGSOC. Specifically, BLTP3A promotes tethering of lysosomes with autophagosomes to drive the elimination of damaged mitochondria. However, dysfunctional BLTP3A promotes damaged mitochondrial accumulation - this generates inflammatory responses through cGAS/STING and elicits elevated orchestration of cellular antitumor immune responses through type I interferon activity. In fact, our new data show that HGSOC specimens expressing polymorphic M1098T BLTP3A demonstrate elevated numbers of effector T cells in these tumor beds. This was observed in association with the emergence of a distinct type I interferon signature in these tumors: likely driven by active cGAS/STING signaling. Additionally, we have clarified that BLTP3A functions as a mitochondrial stress response molecule by associating with autophagic machinery to regulate the turnover of damaged mitochondria though mitophagy. Here, we will utilize our unique mouse models, reagents, and our extensive ovarian tumor bank to further characterize the biology of BTLP3A and its impact on the orchestration of protective immunity in ovarian cancer.
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