MHC II immunogenicity shapes the neoepitope landscape in human tumors.

Jeong Yeon Kim, Hongui Cha, Kyeonghui Kim, Changhwan Sung, Jinhyeon An, Hyoeun Bang, Hyungjoo Kim, Jin Ok Yang, Suhwan Chang, Incheol Shin, Seung-Jae Noh, Inkyung Shin, Dae-Yeon Cho, Se-Hoon Lee, Jung Kyoon Choi
Author Information
  1. Jeong Yeon Kim: Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
  2. Hongui Cha: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  3. Kyeonghui Kim: Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
  4. Changhwan Sung: Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
  5. Jinhyeon An: Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
  6. Hyoeun Bang: Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
  7. Hyungjoo Kim: Penta Medix Co., Ltd., Seongnam-si, Republic of Korea.
  8. Jin Ok Yang: Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
  9. Suhwan Chang: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
  10. Incheol Shin: Department of Life Science, Hanyang University, Seoul, Republic of Korea.
  11. Seung-Jae Noh: Penta Medix Co., Ltd., Seongnam-si, Republic of Korea.
  12. Inkyung Shin: Penta Medix Co., Ltd., Seongnam-si, Republic of Korea.
  13. Dae-Yeon Cho: Penta Medix Co., Ltd., Seongnam-si, Republic of Korea. dabb@pentamedix.com. ORCID
  14. Se-Hoon Lee: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. shlee119@skku.edu. ORCID
  15. Jung Kyoon Choi: Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea. jungkyoon@kaist.ac.kr. ORCID

Abstract

Despite advances in predicting physical peptide-major histocompatibility complex I (pMHC I) binding, it remains challenging to identify functionally immunogenic neoepitopes, especially for MHC II. By using the results of >36,000 immunogenicity assay, we developed a method to identify pMHC whose structural alignment facilitates T cell reaction. Our method predicted neoepitopes for MHC II and MHC I that were responsive to checkpoint blockade when applied to >1,200 samples of various tumor types. To investigate selection by spontaneous immunity at the single epitope level, we analyzed the frequency spectrum of >25 million mutations in >9,000 treatment-naive tumors with >100 immune phenotypes. MHC II immunogenicity specifically lowered variant frequencies in tumors under high immune pressure, particularly with high TCR clonality and MHC II expression. A similar trend was shown for MHC I neoepitopes, but only in particular tissue types. In summary, we report immune selection imposed by MHC II-restricted natural or therapeutic T cell reactivity.

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MeSH Term

Humans
Neoplasms
Epitopes
T-Lymphocytes
Peptides

Chemicals

Epitopes
Peptides

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