Cholesterol efflux from C1QB-expressing macrophages is associated with resistance to chimeric antigen receptor T cell therapy in primary refractory diffuse large B cell lymphoma

Zi-Xun Yan, Yan Dong, Niu Qiao, Yi-Lun Zhang, Wen Wu, Yue Zhu, Li Wang, Shu Cheng, Peng-Peng Xu, Zi-Song Zhou, Ling-Shuang Sheng () and Wei-Li Zhao ()
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Zi-Xun Yan: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yan Dong: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Niu Qiao: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yi-Lun Zhang: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Wen Wu: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yue Zhu: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Li Wang: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Shu Cheng: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Peng-Peng Xu: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Zi-Song Zhou: JW Therapeutics (Shanghai) Co. Ltd
Ling-Shuang Sheng: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Wei-Li Zhao: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated promising efficacy in early trials for relapsed/refractory diffuse large B cell lymphoma (DLBCL). However, its efficacy in treating primary refractory DLBCL has not been comprehensively investigated, and the underlying resistance mechanisms remain unclear. Here, we report the outcomes of a phase I, open-label, single-arm clinical trial of relmacabtagene autoleucel (relma-cel), a CD19-targeted CAR-T cell product, with safety and efficacy as primary endpoints. Among the 12 enrolled patients, 8 experienced grade 4 hematologic toxicity of treatment-emergent adverse event. No grade ≥3 cytokine release syndrome or neurotoxicity occurred. Single-cell RNA sequencing revealed an increase proportion of C1QB-expressing macrophages in patients with progressive disease before CAR-T cell therapy. Cholesterol efflux from M2 macrophages was found to inhibit CAR-T cells cytotoxicity by inducing an immunosuppressive state in CD8+ T cells, leading to their exhaustion. Possible interactions between macrophages and CD8+ T cells, mediating lipid metabolism (AFR1-FAS), immune checkpoint activation, and T cell exhaustion (LGALS9-HAVCR2, CD86-CTLA4, and NECTIN2-TIGIT) were enhanced during disease progression. These findings suggest that cholesterol efflux from macrophages may trigger CD8+ T cell exhaustion, providing a rationale for metabolic reprogramming to counteract CAR-T treatment failure. Chinadrugtrials.org.cn identifier: CTR20200376.

Date: 2024
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DOI: 10.1038/s41467-024-49495-4

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