A signal peptide derived from Hsp60 induces protective cytotoxic T lymphocyte immunity against lymphoid malignancies independently of TAP and classical MHC-I

Xun-Rui Chen; Hai-Hua Yuan; Jia-Hui Guo; Wen-Ying Zhang; Qian-Qian Li; Guo-Ding Huang; Yan-Jie Zhang; Bin Jiang; Feng Liu

doi:10.1016/j.canlet.2020.08.016

A signal peptide derived from Hsp60 induces protective cytotoxic T lymphocyte immunity against lymphoid malignancies independently of TAP and classical MHC-I

Cancer Lett. 2020 Dec 1:494:47-57. doi: 10.1016/j.canlet.2020.08.016. Epub 2020 Aug 20.

Authors

Xun-Rui Chen¹, Hai-Hua Yuan¹, Jia-Hui Guo¹, Wen-Ying Zhang¹, Qian-Qian Li¹, Guo-Ding Huang², Yan-Jie Zhang³, Bin Jiang⁴, Feng Liu⁵

Affiliations

¹ Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201900, China.
² Oncology Department, Hainan Western Central Hospital, Danzhou, 571700, Hainan Province, China.
³ Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201900, China. Electronic address: zhangyanjie@shsmu.edu.cn.
⁴ Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201900, China. Electronic address: jiangbinwcr@sjtu.edu.cn.
⁵ Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201900, China; Oncology Department, Hainan Western Central Hospital, Danzhou, 571700, Hainan Province, China. Electronic address: liufeng@shsmu.edu.cn.

PMID: 32829008
DOI: 10.1016/j.canlet.2020.08.016

Abstract

Hsp60sp, a signal peptide derived from the leader sequence of heat shock protein 60 kDa (Hsp60), is a Qa-1/HLA-E-binding peptide. We previously showed that Hsp60sp-specific CD8⁺ T cells are involved in the immunoregulation of autoimmune diseases by controlling the response of self-reactive lymphocytes. Here, we report that Hsp60sp-specific CD8⁺ T cells killed malignant lymphocytes in vitro independently of transporter associated with antigen processing (TAP) and classical MHC-I expression. Induction of this cytotoxic T lymphocyte (CTL) response in vivo, either by adoptive transfer of in vitro-amplified CTLs or peptide-loaded dendritic cell immunization, resulted in effective control of lymphoid tumors, including TAP- or classical MHC-I-deficient cells. Hsp60sp-specific immune activation combined with programmed cell death protein 1 (PD-1) blocking synergistically restrained mouse lymphoma development. Importantly, Hsp60sp-specific CD8⁺ T cells did not negatively affect normal tissues and cells. Our data suggest that Hsp60sp-based immunotherapy is an inviting strategy to control lymphoid malignancies.

Keywords: HLA-E; Hsp60sp; Immunoescape; Immunotherapy; Lymphoma; Qa-1.

Publication types

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

MeSH terms

Animals
Antigen Presentation
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / transplantation
Cell Line
Chaperonin 60 / chemistry*
Chaperonin 60 / immunology
Combined Modality Therapy
Dendritic Cells / immunology*
Dendritic Cells / transplantation
Female
Histocompatibility Antigens Class I / metabolism
Immune Checkpoint Inhibitors / administration & dosage*
Immune Checkpoint Inhibitors / pharmacology
Immunization
Lymphoma / immunology
Lymphoma / therapy*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mitochondrial Proteins / chemistry*
Mitochondrial Proteins / immunology
Protein Sorting Signals / physiology*
T-Lymphocytes, Cytotoxic / immunology*
T-Lymphocytes, Cytotoxic / transplantation

Substances

Chaperonin 60
Histocompatibility Antigens Class I
Hspd1 protein, mouse
Immune Checkpoint Inhibitors
Mitochondrial Proteins
Protein Sorting Signals