Institute of Organic Chemistry, Johannes Gutenberg University, Mainz, Germany.
Institute for Immunology, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany.
Nat Commun. 2021 Oct 13;12(1):5981. doi: 10.1038/s41467-021-26269-w.
The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.
黑色素瘤酸性肿瘤微环境通过上调肿瘤浸润单核细胞中的环腺苷酸 (cAMP) 来驱动免疫逃逸。在这里，我们表明，从聚（肌氨酸）嵌段聚（L-谷氨酸γ-苄酯）（多肽）共聚物胶束中释放出无毒浓度的腺苷酸环化酶 (AC) 抑制剂可恢复抗肿瘤免疫。与选择性、非治疗性调节性 T 细胞耗竭相结合，AC 抑制剂胶束可完全缓解已建立的 B16-F10-OVA 肿瘤。对黑色素瘤浸润免疫细胞的单细胞测序表明，AC 抑制剂胶束减少了抗炎性髓样细胞的数量和 T 细胞上的检查点受体表达。因此，AC 抑制剂胶束代表了一种免疫治疗措施，可对抗黑色素瘤的免疫逃逸。
