HLA-G and HLA-E Immune Checkpoints Are Widely Expressed in Ewing Sarcoma but Have Limited Functional Impact on the Effector Functions of Antigen-Specific CAR T Cells

Cancers

Simone König¹  Sareetha Kailayangiri²  Jutta Meltzer²  Nicole Farwick²  Bianca Altvater²  Maike Flügge²  Claudia Rossig²  Katja Urban²  Lina F. Pérez Lanuza²  Lea Greune²  Wolfgang Hartmann³  Dennis Görlich⁴ 

[1] Core Unit Proteomics, Interdisciplinary Center for Clinical Research, 48149 Muenster, Germany;Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, 48149 Muenster, Germany;Gerhard-Domagk-Institute of Pathology, University of Muenster, 48149 Muenster, Germany;Institute of Biostatistics and Clinical Research, University of Muenster, 48149 Muenster, Germany;

关键词: cellular immunotherapy;    checkpoint inhibitors;    Ewing sarcoma;    HLA-G;    HLA-E;   

DOI  :  10.3390/cancers13122857

来源: DOAJ

【 摘 要 】

Immune-inhibitory barriers in the tumor microenvironment of solid cancers counteract effective T cell therapies. Based on our finding that Ewing sarcomas (EwS) respond to chimeric antigen receptor (CAR) gene-modified effector cells through upregulation of human leukocyte antigen G (HLA-G), we hypothesized that nonclassical HLA molecules, HLA-G and HLA-E, contribute to immune escape of EwS. Here, we demonstrate that HLA-G isotype G1 expression on EwS cells does not directly impair cytolysis by G_D2-specific CAR T cells (CART), whereas HLA-G1 on myeloid bystander cells reduces CART degranulation responses against EwS cells. HLA-E was induced in EwS cells by IFN-γ stimulation in vitro and by G_D2-specific CART treatment in vivo and was detected on tumor cells or infiltrating myeloid cells in a majority of human EwS biopsies. Interaction of HLA-E-positive EwS cells with G_D2-specific CART induced upregulation of HLA-E receptor NKG2A. However, HLA-E expressed by EwS tumor cells or by myeloid bystander cells both failed to reduce antitumor effector functions of CART. We conclude that non-classical HLA molecules are expressed in EwS under inflammatory conditions, but have limited functional impact on antigen-specific T cells, arguing against a relevant therapeutic benefit from combining CART therapy with HLA-G or HLA-E checkpoint blockade in this cancer.

【 授权许可】

Unknown