小柯机器人

德国德累斯顿工业大学Sebastian Zeissig课题组发现，骨髓钙调磷酸酶-NFAT途径的微生物群依赖性激活抑制结直肠癌中B7H3和B7H4依赖性的抗肿瘤免疫力。2022年3月31日，《免疫》杂志在线发表了这项成果。

研究人员发现，小鼠骨髓特异性缺失钙调磷酸酶激活了保护性的CD8⁺ T细胞反应，并抑制了结直肠癌（CRC）的生长。髓系细胞对微生物的感应促进了钙调磷酸酶和NFAT依赖的白细胞介素6（IL-6）的释放，肿瘤细胞对共抑制分子B7H3和B7H4的表达，以及对CD8⁺ T细胞依赖的抗肿瘤免疫的抑制。因此，靶向这一途径的成员激活了保护性的CD8⁺ T细胞反应，抑制了原发性和转移性CRC的生长。B7H3和B7H4被大多数人类原发性CRC和转移瘤所表达，这与肿瘤浸润性CD8⁺ T细胞数量少和生存率低有关。因此，一个微生物群、钙调磷酸酶和B7H3/B7H4依赖性的途径控制着抗肿瘤免疫力，这揭示了在微卫星稳定的CRC中免疫检查点抑制的额外靶标。

据悉，肠道肿瘤细胞的细菌感应通过细胞内在的钙调磷酸酶-NFAT轴的激活促进了肿瘤的生长，但该途径在其他肠道细胞中的作用仍不清楚。

附：英文原文

Title: Microbiota-dependent activation of the myeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumor immunity in colorectal cancer

Author: Kenneth Peuker, Anne Strigli, Daniele V.F. Tauriello, Alexander Hendricks, Witigo von Schnfels, Greta Burmeister, Mario Brosch, Alexander Herrmann, Sandra Krüger, Jessica Nitsche, Lea Juni, Marc Marius Geissler, Andreas Hiergeist, André Gessner, Jakob Wirbel, Ruby Priyadarshini Ponnudurai, Antje Tunger, Rebekka Wehner, Daniel E. Stange, Jürgen Weitz, Daniela E. Aust, Gustavo B. Baretton, Marc Schmitz, Christoph Rcken, Jochen Hampe, Sebastian Hinz, Georg Zeller, Triantafyllos Chavakis, Clemens Schafmayer, Eduard Batlle, Sebastian Zeissig

Issue&Volume: 2022-03-31

Abstract: Bacterial sensing by intestinal tumor cells contributes to tumor growth through cell-intrinsicactivation of the calcineurin-NFAT axis, but the role of this pathway in other intestinalcells remains unclear. Here, we found that myeloid-specific deletion of calcineurinin mice activated protective CD8+ T cell responses and inhibited colorectal cancer (CRC) growth. Microbial sensingby myeloid cells promoted calcineurin- and NFAT-dependent interleukin 6 (IL-6) release,expression of the co-inhibitory molecules B7H3 and B7H4 by tumor cells, and inhibitionof CD8+ T cell-dependent anti-tumor immunity. Accordingly, targeting members of this pathwayactivated protective CD8+ T cell responses and inhibited primary and metastatic CRC growth. B7H3 and B7H4 wereexpressed by the majority of human primary CRCs and metastases, which was associatedwith low numbers of tumor-infiltrating CD8+ T cells and poor survival. Therefore, a microbiota-, calcineurin-, and B7H3/B7H4-dependentpathway controls anti-tumor immunity, revealing additional targets for immune checkpointinhibition in microsatellite-stable CRC.

DOI: 10.1016/j.immuni.2022.03.008

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00131-5

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