CTLA-4 inhibition facilitates follicular T-B cell interaction and the production of tumor-specific antibodies
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA845790 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19540620.fastq.gz | Fastqsanger.gz | |||
| SRR19540621.fastq.gz | Fastqsanger.gz | |||
| SRR19540622.fastq.gz | Fastqsanger.gz | |||
| SRR19540623.fastq.gz | Fastqsanger.gz | |||
| SRR19540624.fastq.gz | Fastqsanger.gz |
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Project description:Immune checkpoint inhibitors (ICIs) induce activation and expansion of cytotoxic T cells. To depict a comprehensive immune cell landscape reshaped by the CTLA-4 checkpoint inhibitor, we performed single-cell RNA sequencing in a mouse syngeneic tumor transplant model. After CTLA-4 inhibition, tumor regression was accompanied by massive immune cell expansion, especially in T and B cells. We found that B cells in tumor transplant represented follicular, germinal center, and plasma B cells, some of which shared identical B cell receptor clonotypes and possessed tumor reactivity. Furthermore, the posttreatment tumor contained a tertiary lymphoid structure with intermingled T and B cells. These data suggest germinal center formation within the tumor mass and in situ differentiation of tumor-specific plasma cells. Taken together, our data provide a panoramic view of the immune microenvironment after CTLA-4 inhibition and suggest a role for tumor-specific B cells in anti-tumor immunity.
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Project description:Despite the clinical success of checkpoints inhibitors, a significant gap still exists in our understanding of their in vivo mechanism of action, thus limiting the rational development of next generation agents. Amongst these, anti-CTLA-4 antibodies were originally developed to block inhibitory signals into activated effector T cells. However, several recent studies have demonstrated that depletion of regulatory T cells expressing high levels of CTLA-4 is critical to anti-CTLA-4 anti-tumor activity. Whereas the mechanism of action remains controversial, the emerging data support clinical development of new antibodies with enhanced killing activity. Here, using single-cell RNA sequencing in in vivo and in vitro mouse models, we sought to dissect the impact of anti-CTLA-4 blocking, Treg depleting, and FcR engaging activity on the immune responses within tumors. We observed a rapid remodeling of the innate immune landscape as early as 24-hours post-treatment. Immune remodeling was driven mainly by FcγR-engagement, and not by Treg depletion or CTLA-4 blockade, and included reduction of suppressive macrophages and activation of type-I interferon signaling. Our findings indicate that FcγR engagement and innate immune remodeling are involved in successful anti-CTLA-4 treatment, supporting further development of optimized immunotherapy agents with these features.
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Project description:The microbiota colonizes each barrier site and broadly controls host physiology. However, when uncontrolled, microbial colonists can also promote inflammation and induce systemic infection. The unique strategies employed at each barrier tissue to control the coexistence of the host with its microbiota remain largely elusive. Here we uncover that, within the skin, host-microbiota symbiosis depends on the remarkable ability of the skin to act as an autonomous lymphoid organ. Notably, an encounter with a new skin commensal promotes two parallel responses, both under the control of Langerhans cells. On one hand, skin commensals induce the formation of classical germinal centers within secondary lymphoid organs associated with IgG1 and IgG3 antibody responses. On the other hand, microbial colonization also leads to the development of tertiary lymphoid organs within the skin itself that can locally sustain and mature IgG2b and IgG2c responses. These phenomena are supported, at least in part, by the ability of the skin regulatory T cells to convert into T follicular helper cells that accumulate within organized tertiary lymphoid organs within the dermis. Skin autonomous production of antibodies is sufficient to control local commensal colonization as well as subsequent systemic infection with the same microbe. Collectively, these results reveal a striking compartmentalization of humoral responses to the microbiota. Further, this work uncovers a previously unappreciated function for the skin as a compartment able to develop, in the absence of inflammation, powerful and long-lived antibody responses independently of secondary lymphoid organs.
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Project description:Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with B7 proteins CD80 and CD86. CTLA-4 is the first immune checkpoint targeted with a monoclonal antibody inhibitor. Checkpoint inhibitors have generated durable responses in many cancer patients, representing a revolutionary milestone in cancer immunotherapy. However, therapeutic efficacy is limited to a small portion of patients, and immune-related adverse events are noteworthy, especially for monoclonal antibodies directed against CTLA-4. Previously, small molecules have been developed to impair the CTLA-4: CD80 interaction; however, they directly targeted CD80 and not CTLA-4. In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to target CTLA-4. We validated primary hits with biochemical, biophysical, immunological, and experimental animal assays. We then optimized lead compounds and obtained inhibitors with an inhibitory concentration of 1 micromole in disrupting the interaction between CTLA-4 and CD80. Unlike ipilimumab, these small molecules did not degrade CTLA-4. Several compounds inhibited tumor development prophylactically and therapeutically in syngeneic and CTLA-4-humanized mice. This project supports an AI-based framework in designing small molecules targeting immune checkpoints for cancer therapy.
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Project description:The importance of CTLA-4 regulation of T cell function is well recognized. Studies here report the expression of this immune-regulator in murine B-1a cells, and demonstrate the critical roles CTLA-4 plays in maintaining self-tolerance through regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. By selectively deleting CTLA-4 from B cells, we show that the conditional knockout mice spontaneously generate T follicular helper (Tfh) cells and germinal centers (GC) in spleen; produce autoantibodies; and, later in life, develop autoimmune pathologies. This impaired immune homeostasis results from B-1a dysfunction when they lose CTLA-4. Thus, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate to antigen-presenting cells and, when reconstituted in normal congenic recipients, induce GC responses and Tfh cells expressing a highly selected repertoire. These findings introduce CTLA-4 regulation of B-1a as a crucial immune-regulatory mechanism.
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Project description:Transcriptome of murine gastric cancer treated with anti-IL-17, PD-1 or CTLA-4 antibodies.
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Project description:CTLA-4 is thought to inhibit effector T cells both intrinsically, by competing with CD28 for B7 ligands, and extrinsically, through the action of regulatory T cells. We studied in vivo responses of normal and CTLA-4-deficient antigen-specific murine effector CD4+ T cells. In order to do these studies in a physiological model of immunity to foreign antigen, we transferred small numbers of congenically marked RAG2-deficient 5C.C7 T cells with either a normal or knockout allele of CTLA-4 into normal syngeneic B10.A recipient mice. The T cells were then activated by immunization with MCC peptide and LPS. To look for transcriptional signatures of negative regulation of T cell responses by CTLA-4, we used microarray analysis to compare transcripts in wild type and CTLA-4 KO 5C.C7 T cells four days after immunization. This is the first instance in which differences are observed in extent of accumulation of wild type and CTLA-4 KO 5C.C7 T cells. To compare the gene expression profile between wild type and CTLA-4 KO adoptively transferred T cells 4 days after immunization.
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Project description:The MR is an endocytic receptor, which plays an important role in serum homeostasis and antigen presentation. In this study, we firstly describe an important role of the MR as a direct regulator of CD8+ T cell activity. We could demonstrate that the presence of the MR on DCs impaired the cytotoxicity of activated CD8+ T cells both in vitro and in vivo. This regulatory effect was mediated by a direct interaction of the MR with CD45 on the T cells surface, which abolished CD45 activity. MR-mediated suppression of CD45 resulted in the up-regulation of the inhibitory molecule CTLA-4, which in turn was responsible for the reduced T cell activity. MR-mediated inactivation of CD45, up-regulation of CTLA-4 and T cell inactivation could be circumvented by increased signaling via CD28, which was achieved by DC maturation. These implications point out an important role of the MR in maintaining the balance between tolerance and immunity and might have pivotal implications for the development of vaccination strategies aimed at dampening adaptive immunity. DesTCR T cells were incubated with MR-deficient DCs in the presence of FcMR or isotype controls for the indicated time points. Afterwards, CD8+ T cells were isolated by cell sorting (FACSAria), and immediately lysed in Trizol (Invitrogen) before storage at -80°C for RNA isolation.
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Project description:Host-microbiota interaction is regulated by skin autonomous production of antibodies
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