TRIB3 reduces CD8+ T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer
TRIB3 reduces CD8+ T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer
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DOI：
10.1126/scitranslmed.abf0992
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发表时间：
2022-01-05
影响因子：
17.1
通讯作者：
Hua, Fang
中科院分区：
文献类型：
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作者：
Shang, Shuang;Yang, Yu-wei;Hua, Fang
结直肠癌（CRC）中的高CD 8（+）T细胞浸润应表明良好的预后和对免疫治疗的满意反应;然而，绝大多数CRC患者由于T细胞浸润不良而无法从免疫治疗中获益。因此，需要更好地了解CRC肿瘤中T细胞排斥的机制。Tribbles同源物3（TRIB 3）被认为是一种癌蛋白，但其在调节抗肿瘤免疫应答中的作用尚未确定。在这里，我们证明了TRIB 3在各种CRC小鼠模型中抑制CD 8（+）T细胞浸润。我们发现TRIB 3被乙酰转移酶P300乙酰化，这抑制了TRIB 3的泛素化和随后的蛋白酶体降解。异位表达的TRIB 3通过增强表皮生长因子受体信号传导途径抑制信号转导和转录激活因子1（STAT 1）活化和STAT 1介导的CXCL 10转录，导致肿瘤浸润性T细胞减少。用P300抑制剂对Trib 3进行基因消融或药理学加速Trib 3降解增加了T细胞募集，并使CRC对免疫检查点阻断疗法敏感。这些发现将TRIB 3鉴定为CRCs中CD 8（+）T细胞浸润的负调节剂，突出了治疗免疫学上“冷”CRCs的潜在治疗靶点。
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.