Sci Transl Med Hua Fang / Zhang Haizeng discovers a potential therapeutic target for colorectal cancer: TRIB3 reduces CD8+ T cell infiltration and induces immune evasion

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High CD8+ T cell infiltration in iNature colorectal cancer (CRC) should suggest a favorable prognosis and a satisfactory response to immunotherapy; however, the vast majority of CRC patients do not benefit from immunotherapy due to poor T cell infiltration
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Therefore, a better understanding of the mechanisms by which T cells are excluded from CRC tumors is needed
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Tribbles homology 3 (TRIB3) is considered an oncoprotein, but its role in regulating antitumor immune responses has not been established
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On January 5, 2022, Hua Fang, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, and Zhang Haizeng, Chinese Academy of Medical Sciences/Peking Union Medical College National Cancer Center/National Cancer Clinical Research Center/Tumor Hospital Zhang Haizeng jointly communicated in Science Translational Medicine (IF= 18) Published online research paper titled "TRIB3 reduces CD8+ T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer", which demonstrated that TRIB3 inhibits CD8+ T cell infiltration in various CRC mouse models
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This study found that TRIB3 is acetylated by the acetyltransferase P300, thereby inhibiting TRIB3 ubiquitination and subsequent proteasomal degradation
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Ectopically expressed TRIB3 inhibits signal transducer and activator of transcription 1 (STAT1) activation and STAT1-mediated CXCL10 transcription by enhancing the epidermal growth factor receptor signaling pathway, resulting in a decrease in tumor-infiltrating T cells
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Genetic ablation of Trib3 or pharmacological acceleration of TRIB3 degradation with P300 inhibitors increases T cell recruitment and sensitizes CRC to immune checkpoint blockade therapy
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Taken together, these findings identify TRIB3 as a negative regulator of CD8+ T cell infiltration in CRC, highlighting a potential therapeutic target for the treatment of immunologically "cold" CRC
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Therapeutic targeting of immune checkpoint molecules has attracted great interest due to their potential to treat a variety of solid tumors, such as melanoma and lung cancer
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However, for colorectal cancer (CRC), only about 15% of patients benefit from immune checkpoint blockade (ICB) therapy
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There is increasing evidence that immune infiltration can better determine patient response to immunotherapy than tumors' microsatellite instability (MSI) status, an existing predictive biomarker for ICB treatment
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For stage I to III colorectal cancer, the immune score is emerging as a more important independent predictor and outperforms traditional tumor, lymph node, and metastasis (TNM) classification
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For patients with stage IV metastatic colorectal cancer, the metastatic immune score also predicted the risk of recurrence and death
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Dysregulation of T cell trafficking to tumor tissue is one of the reasons for the lack of tumor T cell infiltration
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In some cases, tumor cells disrupt the expression of chemokines, thereby deregulating effector T cell recruitment
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Identifying these immunological changes and their underlying mechanisms in CRC opens up new possibilities for improving CRC patients who may benefit from ICB therapy
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Tribbles homologue 3 (TRIB3) is an oncoprotein in both solid tumors and hematological malignancies
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From the perspective of cancer cells' inherent oncogenic activity, TRIB3 promotes CRC stemness and progression by enhancing β-catenin/transcription factor 4 (TCF4) transcriptional activity
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There is increasing evidence that TRIB3 has a regulatory function in immune responses
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TRIB3 impairs Toll-like receptor 2-mediated nuclear factor κB (NF-κB) activation and chemokine induction in response to Helicobacter pylori lipopolysaccharide
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As a metabolic stress sensor, TRIB3 inhibits the production of pro-inflammatory cytokines in macrophages in response to oxidative LDL stimulation
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However, the exact role of TRIB3 in the antitumor immune response is unclear
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Epidemiological and clinical evidence suggests that patients with diabetes mellitus (DM) are at increased risk for a variety of cancers, including CRC
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In addition, cancer has surpassed vascular disease as the leading cause of excess diabetes-related death
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Oversupply of energy sources and overactivation of mitogenic signaling due to hyperglycemia and hyperinsulinemia due to DM are two possible but insufficient explanations for the increased cancer risk
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TRIB3 is highly induced under diabetic stress and acts as a molecular link between diabetes and cancer by blocking autophagic flux
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From this perspective, the co-occurrence of diabetes and CRC may be an appropriate pathological model to explore not only the immune function of TRIB3 but also provide clues on how diabetic stress suppresses antitumor immune responses
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In this study, acetylation of lysine (K) 240 of CRC-expressed TRIB3 by histone acetyltransferase P300 was found to increase the stability of TRIB3
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This impairs T cell infiltration into tumor tissue by inhibiting the signal transducer and activator of transcription 1 (STAT1)–CXC motif chemokine ligand 10 (CXCL10) axis in CRC
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Furthermore, this study reveals the potential of targeting TRIB3 stability as a strategy to enhance the efficacy of ICB therapy
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