CD79A/CD40 共刺激结构域富集 T 细胞增殖和记忆基因特征增强 CD19 CAR-T 细胞功能

CD19 chimeric antigen receptor (CAR) T-cells have demonstrated remarkable outcomes in B-cell malignancies. Recently, the novel CD19CAR-T cells incorporated with B-cell costimulatory molecules of CD79A/CD40 demonstrated superior antitumor activity in the B-cell lymphoma model compared with CD28 or 4-1BB.

Here, we investigated the intrinsic transcriptional gene underlying the functional advantage of CD19. 79A. 40z CAR-T cells following CD19 antigen exposure using transcriptome analysis compared to CD28 or 4-1BB.

Notably, CD19. 79A. 40z CAR-T cells up-regulated genes involved in T-cell activation, T-cell proliferation, and NF- B signaling, whereas down-regulated genes associated with T-cell exhaustion and apoptosis. Interestingly, CD19. 79A. 40z CAR- and CD19. BBz CAR-T cells were enriched in almost similar pathways.

Furthermore, gene set enrichment analysis demonstrated the enrichment of genes, which were previously identified to correlate with T-cell proliferation, interferon signaling pathway, and na ve and memory T-cell signatures, and down-regulated T-cell exhaustion genes in CD79A/CD40, compared with the T-cell costimulatory domain. The CD19. 79A. 40z CAR-T cells also up-regulated genes related to glycolysis and fatty acid metabolism, which are necessary to drive T-cell proliferation and differentiation compared with conventional CD19CAR-T cells.

Our study provides a comprehensive insight into the understanding of gene signatures that potentiates the superior antitumor functions by CD19CAR-T cells incorporated with the CD79A/CD40 costimulatory domain.