Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation

Wanzun Lin; Li Chen; Haojiong Zhang; Xianxin Qiu; Qingting Huang; Fangzhu Wan; Ziyu Le; Shikai Geng; Anlan Zhang; Sufang Qiu; Long Chen; Lin Kong; Jiade J Lu

doi:10.1038/s41467-022-35710-7

Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation

Nat Commun. 2023 Jan 17;14(1):265. doi: 10.1038/s41467-022-35710-7.

Authors

Wanzun Lin^{1

2

3}, Li Chen^{1

2

3}, Haojiong Zhang^{2

3

4}, Xianxin Qiu^{2

3

4}, Qingting Huang^{2

3

4}, Fangzhu Wan^{1

2

3}, Ziyu Le^{1

2

3}, Shikai Geng^{1

2

3}, Anlan Zhang^{1

2

3}, Sufang Qiu⁵, Long Chen⁶, Lin Kong^{7

8

9}, Jiade J Lu^{10

11

12}

Affiliations

¹ Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, 201321, China.
² Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China.
³ Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China.
⁴ Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China.
⁵ Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 35005, China.
⁶ Department of Neurosurgery & Neurocritical care, Huashan Hospital, Fudan University, Shanghai, China.
⁷ Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, 201321, China. [email protected].
⁸ Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China. [email protected].
⁹ Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China. [email protected].
¹⁰ Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China. [email protected].
¹¹ Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China. [email protected].
¹² Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China. [email protected].

Abstract

The recently described role of RNA methylation in regulating immune cell infiltration into tumors has attracted interest, given its potential impact on immunotherapy response. YTHDF1 is a versatile and powerful m6A reader, but the understanding of its impact on immune evasion is limited. Here, we reveal that tumor-intrinsic YTHDF1 drives immune evasion and immune checkpoint inhibitor (ICI) resistance. Additionally, YTHDF1 deficiency converts cold tumors into responsive hot tumors, which improves ICI efficacy. Mechanistically, YTHDF1 deficiency inhibits the translation of lysosomal genes and limits lysosomal proteolysis of the major histocompatibility complex class I (MHC-I) and antigens, ultimately restoring tumor immune surveillance. In addition, we design a system for exosome-mediated CRISPR/Cas9 delivery to target YTHDF1 in vivo, resulting in YTHDF1 depletion and antitumor activity. Our findings elucidate the role of tumor-intrinsic YTHDF1 in driving immune evasion and its underlying mechanism.

Publication types

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

MeSH terms

Animals
HLA Antigens
Histocompatibility Antigens Class I / metabolism
Immune Checkpoint Inhibitors* / pharmacology
Immune Evasion*
Neoplasms* / drug therapy
Neoplasms* / genetics
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism

Substances

Histocompatibility Antigens Class I
HLA Antigens
Immune Checkpoint Inhibitors
RNA-Binding Proteins