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

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

doi:10.1038/s41598-023-46254-1

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

Sci Rep. 2023 Nov 9;13(1):19440. doi: 10.1038/s41598-023-46254-1.

Authors

Kevin Chih-Yang Huang^{1

2

3}, Tao-Wei Ke^{4

5}, Jia-Yi Chen^{1

2

6}, Wei-Ze Hong^{1

2

6}, Shu-Fen Chiang⁷, Chia-Ying Lai^{1

2

6}, Tsung-Wei Chen⁸, Pei-Chen Yang⁶, Liang-Chi Chen⁹, Ji-An Liang^{10

11}, William Tzu-Liang Chen^{12

13

14}, K S Clifford Chao^{15

16

17}

Affiliations

¹ Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 40402, Taiwan, ROC.
² Translation Research Core, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC.
³ Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 40402, Taiwan, ROC.
⁴ Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC.
⁵ School of Chinese Medicine and Graduate Institute of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan, ROC.
⁶ Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC.
⁷ Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung, 42055, Taiwan, ROC.
⁸ Department of Pathology, Asia University Hospital, Asia University, Taichung, 41354, Taiwan, ROC.
⁹ Department of Pathology, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC.
¹⁰ Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan, ROC.
¹¹ Department of Radiotherapy, School of Medicine, China Medical University, Taichung, 40402, Taiwan, ROC.
¹² Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC. wtchen@mail.cmuh.org.tw.
¹³ Department of Colorectal Surgery, China Medical University HsinChu Hospital, China Medical University, HsinChu, 302, Taiwan, ROC. wtchen@mail.cmuh.org.tw.
¹⁴ Department of Surgery, School of Medicine, China Medical University, Taichung, 40402, Taiwan, ROC. wtchen@mail.cmuh.org.tw.
¹⁵ Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC. d94032@mail.cmuh.org.tw.
¹⁶ Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan, ROC. d94032@mail.cmuh.org.tw.
¹⁷ Department of Radiotherapy, School of Medicine, China Medical University, Taichung, 40402, Taiwan, ROC. d94032@mail.cmuh.org.tw.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma*
Colonic Neoplasms* / pathology
HMGB1 Protein* / genetics
HMGB1 Protein* / metabolism
Humans
Oxaliplatin / therapeutic use
Toll-Like Receptor 1 / genetics
Tumor Microenvironment

Substances

Toll-Like Receptor 1
HMGB1 Protein
Oxaliplatin