Propionate promotes MHC class I antigen presentation and anti-tumor immunity
(1) Li S (2) Guo D (3) Yang Q (4) Cao Y (5) Dong Y (6) Jiang X (7) Tian X (8) Nie D (9) Wu L (10) Wu Q (11) He X (12) Hu Y (13) Zhu R (14) Zhu N (15) Luo S (16) Shen Y (17) Wang Y (18) Chi Z (19) Yuan Y (20) Xu D (21) Wang W (22) Ding Y (23) Lu Z
Li et al. found that dietary supplementation with the short-chain fatty acid propionate could be used to stabilize and maintain expression of MHC-I in tumor cells by binding to the E3 ligase STUB1, blocking the K30 and N34 residues, and thus the direct interactions that would lead to STUB1-mediated polyubiquitination and lysosomal degradation of MHC-I. In mice, dietary propionate increased MHC-I on tumor cells, resulting in enhanced CD8+ T cell-mediated antitumor immunity and IFNγ production, which further increased tumor MHC-I. Propionate also improved the efficacy of anti-PD-1, as did the propionate-producing probiotic A. muciniphila.
Contributed by Lauren Hitchings
(1) Li S (2) Guo D (3) Yang Q (4) Cao Y (5) Dong Y (6) Jiang X (7) Tian X (8) Nie D (9) Wu L (10) Wu Q (11) He X (12) Hu Y (13) Zhu R (14) Zhu N (15) Luo S (16) Shen Y (17) Wang Y (18) Chi Z (19) Yuan Y (20) Xu D (21) Wang W (22) Ding Y (23) Lu Z
Li et al. found that dietary supplementation with the short-chain fatty acid propionate could be used to stabilize and maintain expression of MHC-I in tumor cells by binding to the E3 ligase STUB1, blocking the K30 and N34 residues, and thus the direct interactions that would lead to STUB1-mediated polyubiquitination and lysosomal degradation of MHC-I. In mice, dietary propionate increased MHC-I on tumor cells, resulting in enhanced CD8+ T cell-mediated antitumor immunity and IFNγ production, which further increased tumor MHC-I. Propionate also improved the efficacy of anti-PD-1, as did the propionate-producing probiotic A. muciniphila.
Contributed by Lauren Hitchings
ABSTRACT: Defective tumor antigen presentation promotes immune evasion and resistance to immune checkpoint blockade. Here, we identified the short-chain fatty acid propionate as a potent enhancer of major histocompatibility complex class I (MHC class I) antigen presentation. Propionate stabilizes MHC class I on tumor cells, promotes CD8(+) T cell infiltration and activation, and suppresses tumor growth. Mechanistically, the E3 ubiquitin (Ub) ligase STUB1 directly interacts with human leukocyte antigen (HLA)-A to mediate K168/K170 polyubiquitination and subsequent degradation. Propionate directly binds STUB1 through hydrogen bonds involving K30 and N34, residues that overlap with the MHC class I-binding interface. This interaction blocks STUB1-mediated MHC class I polyubiquitination, thereby stabilizing MHC class I, enhancing T cell receptor (TCR) engagement and T cell activation, and restraining tumor growth. Importantly, propionate or the propionate-producing probiotic Akkermansia muciniphila markedly enhanced anti-PD-1 efficacy. These findings uncover a non-metabolic moonlighting function of short-chain fatty acids in regulating tumor immunity and provide a rationale for leveraging dietary propionate or propionate-producing probiotics to enhance immune checkpoint therapy.
Author Info:
(1) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Transl
ational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (2) Department of Gastroenterology, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China. Electronic address: dongguo@shsmu.edu.cn. (3) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (4) Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (5) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China. (6) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (7) Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China. (8) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (9) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (10) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (11) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (12) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (13) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (14) Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang Provincial Clinical Research Center for Cancer, Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China. (15) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (16) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China. (17) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (18) Center for Regeneration and Aging Medicine, The Fourth Affiliated Hospital of School of Medicine, International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang 322000, China. (19) Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang Provincial Clinical Research Center for Cancer, Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China. (20) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. (21) Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China. Electronic address: wam@zju.edu.cn. (22) Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China. Electronic address: dingyuan@zju.edu.cn. (23) Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; The Center for Translational Research, The Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China. Electronic address: zhiminlu@zju.edu.cn.
