Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
BMC Cancer. 2022 Aug 4;22(1):852. doi: 10.1186/s12885-022-09956-9.
Tumor acidosis, a common phenomenon in solid cancers such as breast cancer, is caused by the abnormal metabolism of cancer cells. The low pH affects cells surrounding the cancer, and tumor acidosis has been shown to inhibit the activity of immune cells. Despite many previous studies, the immune surveillance mechanisms are not fully understood. We found that the expression of PD-L1 was significantly increased under conditions of extracellular acidosis in MDA-MB-231 cells. We also confirmed that the increased expression of PD-L1 mediated by extracellular acidosis was decreased when the pH was raised to the normal range. Gene set enrichment analysis (GSEA) of public breast cancer patient databases showed that PD-L1 expression was also highly correlated with IL-6/JAK/STAT3 signaling. Surprisingly, the expression of both phospho-tyrosine STAT3 and PD-L1 was significantly increased under conditions of extracellular acidosis, and inhibition of STAT3 did not increase the expression of PD-L1 even under acidic conditions in MDA-MB-231 cells. Based on these results, we suggest that the expression of PD-L1 is increased by tumor acidosis via activation of STAT3 in MDA-MB-231 cells.
肿瘤酸中毒是乳腺癌等实体瘤中常见的现象，是由癌细胞的异常代谢引起的。低 pH 值会影响癌症周围的细胞，肿瘤酸中毒已被证明会抑制免疫细胞的活性。尽管之前有许多研究，但免疫监视机制仍未完全了解。我们发现 MDA-MB-231 细胞在细胞外酸中毒条件下 PD-L1 的表达显著增加。我们还证实，当 pH 值升高到正常范围时，细胞外酸中毒介导的 PD-L1 表达增加减少。公共乳腺癌患者数据库的基因集富集分析 (GSEA) 表明，PD-L1 表达也与 IL-6/JAK/STAT3 信号高度相关。令人惊讶的是，在细胞外酸中毒条件下，磷酸化酪氨酸 STAT3 和 PD-L1 的表达均显著增加，并且即使在 MDA-MB-231 细胞的酸性条件下抑制 STAT3 也不会增加 PD-L1 的表达。基于这些结果，我们认为在 MDA-MB-231 细胞中，肿瘤酸中毒通过激活 STAT3 增加了 PD-L1 的表达。
