Germline HLA-DQ genotype influences response to CAR T-cell therapy in patients with large B-cell lymphoma

Abstract

CD19-directed chimeric antigen receptor (CAR) T cells have greatly improved the prognosis of relapsed/refractory large B-cell lymphoma (rrLBCL), yet treatment failure occurs in more than half of patients, usually in the first 3 months after treatment. While they primarily act through CAR-dependent, HLA-independent recognition of tumor targets, CAR-T cells may also indirectly contribute to long-term tumor immunosurveillance by stimulating endogenous immunity. We hypothesized that HLA diversity, measured by the HLA evolutionary divergence (HED) metric which reflects the breadth of the immunopeptidome presented to host T cells, could influence antitumor response after CAR T-cell therapy, as seen after immune chekpoint inhibitor treatment. We studied 127 rrLBCL patients treated with commercial CAR-T cells in our center, of whom 50 % achieved durable response. We observed no impact of diversity at any HLA locus, except for HED-DQA1 that was surprisingly negatively associated with response. Analysis of the distribution of HLA-DQ alleles according to clustering of HED values pointed to the DQ1/DQ1 genotype as an independent predictor of durable response and lower incidence of relapse/progression. These findings highlight the unsuspected role of germline HLA-DQ molecules in the response to CAR-T cells and suggest an important contribution of cross-talk between CAR-T cells and endogenous immune cells.