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

• Published in: Nature communications 2024-06, Vol.15 (1), p.5183-16, Article 5183
• Main Authors: Yan, Zi-Xun, Dong, Yan, Qiao, Niu, Zhang, Yi-Lun, Wu, Wen, Zhu, Yue, Wang, Li, Cheng, Shu, Xu, Peng-Peng, Zhou, Zi-Song, Sheng, Ling-Shuang, Zhao, Wei-Li
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 13/31; 13/51; 14; 14/1; 14/5; 38; 38/1; 38/39; 49/47; 49/90; 49/91; 631/250/251/1567; 631/250/251/1574; 631/67/1990/291/1621/1915; 82/51; 96/1; 96/21; 96/31; 96/35; Adult; Aged; Antigens; B-cell lymphoma; CD19 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD86 antigen; Cell activation; Cell therapy; Chimeric antigen receptors; Cholesterol; Cholesterol - metabolism; Clinical trials; CTLA-4 protein; Cytotoxicity; Drug Resistance, Neoplasm; Effectiveness; Efflux; Female; Gene sequencing; Health services; Humanities and Social Sciences; Humans; Immune checkpoint; Immunotherapy, Adoptive - methods; Lipid metabolism; Lipids; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - immunology; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - therapy; Macrophages; Macrophages - immunology; Macrophages - metabolism; Male; Middle Aged; multidisciplinary; Neurotoxicity; Patients; Product safety; Receptors; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; Science; Science (multidisciplinary); Therapy; Toxicity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49495-4

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. Although the efficacy of chimaeric antigen receptor (CAR) T cell therapy has been demonstrated in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), it has not been investigated in primary refractory DLBCL. In this phase I clinical trial, the authors report on the safety and efficacy of relmacabtagene autoleucel, a CD19-specific CAR T cell product, and demonstrate using single-cell RNA sequencing that cholesterol efflux from macrophages may impair CAR T cell responses in this context.