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Human regulatory memory B cells defined by expression of TIM-1 and TIGIT are dysfunctional in Multiple Sclerosis.

ABSTRACT: Regulatory B cells (Bregs) play a pivotal role in suppressing immune responses, yet there is still a lack of cell surface markers that can rigorously identify them. In mouse models for multiple sclerosis (MS), TIM-1 or TIGIT expression on B cells is required for maintaining self-tolerance and regulating autoimmunity to the central nervous system. Here we investigated the activities of human memory B cells that differentially express TIM-1 and TIGIT to determine their potential regulatory function in healthy donors and patients with relapsing-remitting (RR) MS. FACS-sorted TIM-1+/-TIGIT+/- memory B (memB) cells co-cultured with allogenic CD4+ T cells were analyzed for proliferation and induction of inflammatory markers using flow cytometry and cytokine quantification, to determine Th1/Th17 cell differentiation. Transcriptional differences were assessed by SMARTSeq2 RNA sequencing analysis. TIM-1-TIGIT- double negative (DN) memB cells strongly induce T cell proliferation and pro-inflammatory cytokine expression. The TIM-1+ memB cells enabled low levels of CD4+ T cell activation and gave rise to T cells that co-express IL-10 with IFNg and IL-17A or FoxP3. T cells cultured with the TIM-1+TIGIT+ double positive (DP) memB cells exhibited reduced proliferation and IFNg, IL-17A, TNFa, and GM-CSF expression, and exhibited strong regulation in Breg suppression assays. The functional activity suggests the DP memB cells are a bonafide Breg population. However, MS DP memB cells were less inhibitory than HC DP memB cells. A retrospective longitudinal study of anti-CD20 treated patients found that post-treatment DP memB cell frequency and absolute number were associated with response to therapy. Transcriptomic analyses indicated that the dysfunctional MS-derived DP memB/Breg population exhibited increased expression of genes associated with T cell activation and survival (CD80, ZNF10, PIK3CA), and had distinct gene expression compared to the TIGIT+ or TIM-1+ memB cells. These findings demonstrate that TIM-1/TIGIT expressing memory B cell subsets have distinct functionalities. Co-expression of TIM-1 and TIGIT defines a regulatory memory B cell subset that is functionally impaired in MS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261258 | GEO | 2024/05/31

REPOSITORIES: GEO

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Project description:CD19-targeting chimeric antigen receptor (CAR) T cell have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, according to the recent clinical data, a significant portion of patients still do not benefit from the therapy, due various resistance mechanisms including the high expression of multiple inhibitory immune checkpoint receptors on activated CAR-T cells. Studies of checkpoint blockade immunotherapy using monoclonal antibodies have shown that simultaneously targeting inhibitory receptors that are functionally non-redundant can synergistically enhance anti-tumor responses. Here we report a lentiviral two-in-one CAR T approach in which two checkpoint receptors can be downregulated simultaneously by a dual short-hairpin RNA (shRNA) cassette integrated into a CAR vector. Using this system, we evaluated CD19-targeting CAR T cells in the context of four different checkpoint combinations, PD-1/TIM-3, PD-1/LAG-3, PD-1/CTLA-4, and PD-1/TIGIT, and found that the CAR T with PD-1/TIGIT downregulation uniquely exhibited synergistic anti-tumor effect in mouse xenograft models compared to the single PD-1 downregulation and maintained cytolytic and proliferative capacity upon repeated antigen exposure. Importantly, functional and phenotypic analysis of CAR T cells as well as analysis of transcriptomic profiles suggests that downregulation of PD-1 enhances short-term effector function while downregulation of TIGIT is primarily responsible for maintaining a less-differentiated/exhausted state, providing a potential mechanism of the synergy. The PD-1/TIGIT downregulated CAR T cells generated from DLBCL patient-derived T cells following clinically applicable manufacturing process also showed a robust anti-tumor activity and significantly improved persistence in vivo compared to conventional CD19-targeting CAR T cells. Overall, our results demonstrate that the cell-intrinsic PD-1/TIGIT dual downregulation strategy may provide an effective way to overcome the immune checkpoint-mediated resistance in CAR T therapy.

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Human regulatory memory B cells defined by expression of TIM-1 and TIGIT are dysfunctional in Multiple Sclerosis.

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