TIMM8A is associated with dysfunction of immune cell in BRCA and UCEC for predicting anti-PD-L1 therapy efficacy

Abstract

Background TIMM8A is a protein-coding gene located on the X chromosome. There is evidence that TIMM8A plays an important role in mitochondrial morphology and fission. Studies have shown that mitophagy and fission could affect the function of immune cells. However, there is currently no research on this gene’s role in cancer occurrence and progression. Methods TIMM8A expression was analyzed via the Tumor Immune Estimation Resource (TIMER) site and UALCAN database. We evaluated the influence of TIMM8A on clinical prognosis using Kaplan-Meier plotter, the PrognoScan database, and Human Protein Atlas (HPA). The correlations between TIMM8A and cancer immune infiltrates were investigated via TIMER. Tumor Immune Dysfunction and Exclusion (TIDE) was used to evaluate the potential of tumor immune evasion. Functions of TIMM8A mutations and 50 genes significantly associated with TIMM8A mutations in breast cancer (BRCA) and uterine corpus endometrial cancer (UCEC) were analyzed by GO and KEGG in LinkedOmics database. Results We investigated the role of TIMM8A in multiple cancers and found that it was significantly associated with poor prognosis in BRCA and UCEC. After analyzing the effect of TIMM8A on immune infiltration, we found Th2 CD4+ T cells might be a common pathway by which TIMM8A contributed to poor prognosis in BRCA and UCEC. Our results suggested that myeloid-derived suppressor cells (MDSC) and tumor-associated M2 macrophages (TAM M2) might be important factors in immune evasion through T cell rejection in both cancers, and considered TIMM8A as a biomarker to predict the efficacy of this therapy in BRCA and UCEC. The results of TIMM8A enrichment analysis showed us that abnormally expressed TIMM8A might affect the mitochondrial protein in BRCA and UCEC. Conclusions Contributed to illustrating the value of TIMM8A as a prognostic biomarker, our findings suggested that TIMM8A was correlated with prognosis and immune infiltration, including CD8+ T cells, Th2 CD4+ T cells, and macrophages in BRCA and UCEC. In addition, TIMM8A might affect immune infiltration and prognosis in BRCA and UCEC by affecting mitophagy. We believed it could also be a biomarker to predict the efficacy of anti-PD-L1 therapy and proposed to improve the efficacy by eliminating MDSC and TAM M2.

A prognostic exosome-related long non-coding RNAs risk model related to the immune microenvironment and therapeutic responses for patients with liver hepatocellular carcinoma

“…As the mutations of these two genes could be more helpful for immunotherapy prediction [ 29 , 30 ], the mutation frequencies of these two genes will be detected lately to more accurately evaluate their benefits in immunotherapy. Zhu et al showed that the poor treatment outcome of breast cancer may be due to the influence of MDSC and TAM in M2 [ 57 ]. In addition, there was also evidence that MDSC and TAM M2 limited the efficacy of anti-PD-L1 therapy in non-small cell lung cancer [ 58 , 59 ].…”

Independent organelle and organelle—organelle interactions: essential mechanisms for malignant gynecological cancer cell survival

“…The X chromosome protein-coding gene TIMM8A affects mitochondrial autophagy to influence immune infiltration and prognosis in UCEC ( 95 ). Enhanced chemodynamic therapy mediated by cancer-specific catalysts synergize with mitochondrial autophagy inhibition to improve endometrial cancer treatment efficacy ( 96 ).…”