Abstract
Genomic deletion of donor–patient-mismatched HLA alleles in leukemic cells is a major cause of relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Mismatched HLA is frequently lost as an individual allele or a whole region in HLA-class I, however, it is downregulated in HLA-class II. We hypothesized that there might be a difference in T cell recognition capacity against epitopes associated with HLA-class I and HLA-class II and consequently such allogeneic immune pressure induced HLA alterations in leukemic cells. To investigate this, we conducted in vitro experiments with T cell receptor-transduced T (TCR-T) cells. The cytotoxic activity of NY-ESO-1-specific TCR-T cells exhibited similarly against K562 cells with low HLA-A*02:01 expression. However, we demonstrated that the cytokine production against low HLA-DPB1*05:01 expression line decreased gradually from the HLA expression level approximately 2-log lower than normal expressors. Using sort-purified leukemia cells before and after HSCT, we applied the next-generation sequencing, and revealed that there were several marked downregulations of HLA-class II alleles which demonstrated consistently low expression from pre-transplantation. The marked downregulation of HLA-class II may lead to decreased antigen recognition ability of antigen-specific T cells and may be one of immune evasion mechanism associated with HLA-class II downregulation.
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Acknowledgements
The authors wish to acknowledge the technical support provided by Shigenari A and Ito S (Tokai University). This work was supported by grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI (18k08351 to S.T.), Practical Research for Innovative Cancer Control (17ck0106291h0001 to S.T.), and Practical Research Project for Allergic Diseases and Immunology from the Japan Agency for Medical Research and Development (19ek0510022h0003 to S.T. and M.M., and 21ek0510032h0002 to T. Shiina. and M.M.).
Funding
This work was supported by grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI (18k08351 to S.T.), Practical Research for Innovative Cancer Control (17ck0106291h0001 to S.T.), and Practical Research Project for Allergic Diseases and Immunology from the Japan Agency for Medical Research and Development (19ek0510022h0003 to S.T. and M.M., and 21ek0510032h0002 to T. Shiina. and M.M.).
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Conception and design: ST, TS, and MM. Execution of experiments and acquisition of data: YA, TS, ST, TS, RH, TG, and TN. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): YA, TS and ST, and TS and MM. Writing, review, and/or revision of the manuscript: YA, ST, TS, MM, and HK. Administrative, technical, or material support (e.g., reporting or organizing data, constructing plasmids): HH, HK, TS, HA, and HK. Study supervision: ST, TS, MM, and HK.
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H. Kiyoi: Research funding from Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Zenyaku Kogyo Co., Ltd., FUJIFILM Corporation, Daiichi Sankyo Co., Ltd., Astellas Pharma Inc., Otsuka Pharmaceutical Co., Ltd., Perseus Proteomics Inc., Nippon Shinyaku Co., Ltd., Eisai Co., Ltd., Bristol Myers Squibb., Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sanofi K.K., CURED Inc. and AbbVie Inc.; honoraria from Astellas Pharma Inc., and Novartis Pharma K.K. The other authors declare no competing financial interests.
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Adachi, Y., Sakai, T., Terakura, S. et al. Downregulation of HLA class II is associated with relapse after allogeneic stem cell transplantation and alters recognition by antigen-specific T cells. Int J Hematol 115, 371–381 (2022). https://doi.org/10.1007/s12185-021-03273-w
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DOI: https://doi.org/10.1007/s12185-021-03273-w