TIMM8A 与 BRCA 和 UCEC 免疫细胞功能障碍相关，可预测抗 PD-L1 治疗疗效。
TIMM8A is associated with dysfunction of immune cell in BRCA and UCEC for predicting anti-PD-L1 therapy efficacy.
机构信息
Department of Dermatology, The Fourth Hospital of Changsha, Changsha, Hunan, 410000, China.
Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, and Xiangya School of Stomatology, Central South University, Changsha, Hunan, 410008, China.
出版信息
World J Surg Oncol. 2022 Oct 7;20(1):336. doi: 10.1186/s12957-022-02736-6.
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.
背景
TIMM8A 是一个位于 X 染色体上的蛋白编码基因。有证据表明，TIMM8A 在线粒体形态和裂变中发挥重要作用。研究表明，自噬和裂变可能会影响免疫细胞的功能。然而，目前尚无关于该基因在癌症发生和进展中的作用的研究。
方法
通过肿瘤免疫估计资源（TIMER）网站和 UALCAN 数据库分析 TIMM8A 的表达。我们使用 Kaplan-Meier 绘图器、PrognoScan 数据库和人类蛋白质图谱（HPA）评估 TIMM8A 对临床预后的影响。通过 TIMER 研究 TIMM8A 与癌症免疫浸润的相关性。使用肿瘤免疫功能障碍和排斥（TIDE）评估肿瘤免疫逃逸的潜力。在 LinkedOmics 数据库中，通过 GO 和 KEGG 分析 TIMM8A 突变与乳腺癌（BRCA）和子宫体子宫内膜癌（UCEC）中 50 个与 TIMM8A 突变显著相关的基因的功能。
结果
我们研究了 TIMM8A 在多种癌症中的作用，发现它与 BRCA 和 UCEC 的预后不良显著相关。在分析 TIMM8A 对免疫浸润的影响后，我们发现 Th2 CD4+ T 细胞可能是 TIMM8A 导致 BRCA 和 UCEC 预后不良的共同途径。我们的研究结果表明，髓系来源的抑制细胞（MDSC）和肿瘤相关的 M2 巨噬细胞（TAM M2）可能是通过 T 细胞排斥在这两种癌症中实现免疫逃逸的重要因素，并认为 TIMM8A 是预测 BRCA 和 UCEC 这种治疗疗效的生物标志物。TIMM8A 富集分析的结果表明，异常表达的 TIMM8A 可能会影响 BRCA 和 UCEC 中的线粒体蛋白。
结论
我们的研究结果表明，TIMM8A 与 BRCA 和 UCEC 的预后和免疫浸润有关，包括 CD8+ T 细胞、Th2 CD4+ T 细胞和巨噬细胞，为 TIMM8A 作为预后生物标志物的价值提供了证据。此外，TIMM8A 可能通过影响自噬来影响 BRCA 和 UCEC 中的免疫浸润和预后。我们认为它也可以作为预测抗 PD-L1 治疗疗效的生物标志物，并提出通过消除 MDSC 和 TAM M2 来提高疗效。
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