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Dysfunctional TLR1 reduces the therapeutic efficacy of chemotherapy by attenuating HMGB1-mediated antitumor immunity in locally advanced colorectal cancer

التفاصيل البيبلوغرافية
العنوان: Dysfunctional TLR1 reduces the therapeutic efficacy of chemotherapy by attenuating HMGB1-mediated antitumor immunity in locally advanced colorectal cancer
المؤلفون: Kevin Chih-Yang Huang, Tao-Wei Ke, Jia-Yi Chen, Wei-Ze Hong, Shu-Fen Chiang, Chia-Ying Lai, Tsung-Wei Chen, Pei-Chen Yang, Liang-Chi Chen, Ji-An Liang, William Tzu-Liang Chen, K. S. Clifford Chao
المصدر: Scientific Reports, Vol 13, Iss 1, Pp 1-14 (2023)
بيانات النشر: Nature Portfolio, 2023.
سنة النشر: 2023
المجموعة: LCC:Medicine
LCC:Science
مصطلحات موضوعية: Medicine, Science
الوصف: Abstract Regional lymph node metastasis is an important predictor for survival outcome and an indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer. Even with advances in adjuvant chemotherapeutic regimens, 5-year distant metastasis and survival rates are still unsatisfactory. Here, we evaluate the clinical significance of polymorphisms in receptors for HMGB1, which is the hallmark of chemotherapy-induced immunogenic cell death, in patients with stage II–III colon carcinoma (COAD). We found that high cytosolic HMGB1 is elicited in stage III COAD patients who received adjuvant chemotherapy. Patients with the TLR1-N248S polymorphism (rs4833095), which causes loss-of-function in HMGB1-mediated TLR1–TLR2 signaling, may influence the therapeutic efficacy of adjuvant chemotherapy, leading to a high risk of distant metastasis within 5 years [HR = 1.694, 95% CI = 1.063–2.698, p = 0.027], suggesting that TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. We found that defective TLR1 impaired TLR1/2 signaling during dendritic cell (DC) maturation for the antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired their maturation ability by HMGB1 and reduced the secretion of IFNγ from T cells to eradicate tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. In contrast, administration of a TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered a high density of tumor-infiltrating immune cells. We also observed that fewer tumor-infiltrating cytotoxic T lymphocytes were located within the tumor microenvironment in patients bearing the TLR1-N248S polymorphism. Overall, our results suggest that dysfunctional TLR1 may reduce the therapeutic response to adjuvant chemotherapy by impairing HMGB1-mediated DC maturation and attenuating the antitumor immune response in locally advanced colon carcinoma patients.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2045-2322
Relation: https://doaj.org/toc/2045-2322
DOI: 10.1038/s41598-023-46254-1
URL الوصول: https://doaj.org/article/805466ca437449f18933c47295fdf9dd
رقم الأكسشن: edsdoj.805466ca437449f18933c47295fdf9dd
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:20452322
DOI:10.1038/s41598-023-46254-1