CD4(+) CAR-T 细胞中调节性 T 细胞的清除增强抗 CD19 CAR-T 治疗中 CD8(+) CAR-T 细胞的杀肿瘤效应

Chimeric antigen receptor T (CAR-T) cell therapy, which targets CD19 for hematological malignancies, represents a breakthrough in cancer immunotherapy.

However, some patients may develop resistance to CAR-T treatment, underscoring the importance of optimizing CAR-T design to enhance responsiveness.

Here, we investigated the impact of different subpopulations in anti-CD19 CAR-T cells on the tumoricidal effect. Different populations of anti-CD19 CAR-T cells were isolated by magnetic-activated cell sorting (MACS). Their lytic activities on the acute lymphocytic leukemia cell line SUP-B15 and diffuse large B-cell lymphoma EB-3 cell line were examined in a co-culture system.

The anti-tumorigenic outcome of different CAR-T cell compositions was evaluated in a xenograft mouse model of EB-3 cells. CD8 + CAR-T cells exhibited the most potent tumoricidal activity against SUP-B15 and EB-3 cells.

Additionally, CD4 + T helper cells enhanced the lytic effects of CD8 + CAR-T cells by increasing the availability of interleukin-2 (IL-2). Depleting CD25 + Treg (T regulatory) cells from CD4 + CAR-T population further augmented the tumoricidal activity of CD8 + CAR-T cells by preventing IL-2 deprivation. Consistently, in vivo experiments demonstrated that the CD4 + CD25 + Treg population dampened the antitumor activity of CD8 + CAR-T cells, while depletion of Tregs from CD4 + CAR-T cells enhanced the tumoricidal effect.

These findings emphasize the potential role of CAR Treg cells in therapeutic resistance, suggesting that the depletion of Tregs in the anti-CD19 CAR-T population may serve as a strategy to augment the anticancer effect of CD8 + CAR-T cells.