套细胞淋巴瘤中单核细胞固有免疫抑制特征通过 IL-1 通路调控抑制 CAR-T19

CD19-targeted chimeric antigen receptor T cells (CAR-T19) have shown remarkable success in B cell malignancies, but most patients relapse within 1-2 years.

Here, we identified interleukin-1 (IL-1) receptor antagonist (IL-1ra) as a mediator of M2-like macrophage-derived inhibition of CAR-T19 in mantle cell lymphoma (MCL), as well as a potential target to enhance CAR-T19 efficacy. In preclinical models that recapitulated interactions between tumor, macrophages, and T cells, we demonstrated that M2-derived IL-1ra impairs IL-1 signaling and functions of CAR-T19.

These findings were validated using clinical samples from the ZUMA-2 trial that led to the FDA approval of CAR-T19 in MCL. Single-cell RNA sequencing of CAR-T19 products and baseline myeloid cells indicated downregulated IL-1 production, enriched immunosuppressive phenotypes, and IL-1ra upregulation in the non-responder monocytes, as well as impaired IL-1 signaling and T cell functions in the non-responder CAR-T19 products.

Furthermore, our preclinical studies of IL-1 showed enhanced CAR-T antitumor activities. Collectively, these data present a potential role for IL-1 signaling and IL-1ra in CAR-T19 failure.