TRIB3 reduces CD8 + T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer

3 years ago

TRIB3 reduces CD8 + T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer

Shuang Shang, Yu-wei Yang, Fei Chen, Liang Yu, Shuo-hao Shen, Ke Li, Bing Cui, Xiao-Xi Lv, Cheng Zhang, Chen Yang, Jing Liu, Jiao-jiao Yu, Xiao-wei Zhang, Ping-ping Li, Sheng-tao Zhu, Hai-zeng Zhang, Fang Hua

High CD8⁺ T cell infiltration in colorectal cancer (CRC) should suggest a favorable prognosis and a satisfactory response to immunotherapy; however, the vast majority of patients with CRC do not benefit from immunotherapy due to poor T cell infiltration. Therefore, a better understanding of the mechanisms for T cell exclusion from CRC tumors is needed. Tribbles homolog 3 (TRIB3) has been implicated as an oncoprotein, but its role in regulating antitumor immune responses has not been defined. Here, we demonstrated that TRIB3 inhibits CD8⁺ T cell infiltration in various CRC mouse models. We showed that TRIB3 was acetylated by acetyltransferase P300, which inhibited ubiquitination and subsequent proteasomal degradation of TRIB3. Ectopically expressed TRIB3 inhibited signal transducer and activator of transcription 1 (STAT1) activation and STAT1-mediated CXCL10 transcription by enhancing the epidermal growth factor receptor signaling pathway, causing a reduction in tumor-infiltrating T cells. Genetic ablation of Trib3 or pharmacological acceleration of TRIB3 degradation with a P300 inhibitor increased T cell recruitment and sensitized CRCs to immune checkpoint blockade therapy. These findings identified TRIB3 as a negative modulator of CD8⁺ T cell infiltration in CRCs, highlighting a potential therapeutic target for treating immunologically "cold" CRCs.

Publisher URL: https://www.science.org/doi/10.1126/scitranslmed.abf0992

DOI: 10.1126/scitranslmed.abf0992