Downregulation of HLA class II is associated with relapse after allogeneic stem cell transplantation and alters recognition by antigen-specific T cells

• Published in: International journal of hematology 2022-03, Vol.115 (3), p.371-381
• Main Authors: Adachi, Yoshitaka, Sakai, Toshiyasu, Terakura, Seitaro, Shiina, Takashi, Suzuki, Shingo, Hamana, Hiroshi, Kishi, Hiroyuki, Sasazuki, Takehiko, Arase, Hisashi, Hanajiri, Ryo, Goto, Tatsunori, Nishida, Tetsuya, Murata, Makoto, Kiyoi, Hitoshi
• Format: Article
• Language: English
• Subjects: Alleles; Antigens; Cell recognition; Clonal deletion; Cytokines; Cytotoxicity; Down-Regulation; Epitopes; Epitopes - immunology; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Graft vs Leukemia Effect - immunology; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histocompatibility antigen HLA; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - metabolism; Humans; K562 Cells; Leukemia; Leukemia - genetics; Leukemia - immunology; Leukemia - therapy; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Next-generation sequencing; Oncology; Original Article; Recognition; Recurrence; Stem cell transplantation; Stem cells; T cell receptors; T-Lymphocytes - immunology; Transplantation; Transplantation, Homologous
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-021-03273-w

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.