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Anti-VEGF treatment enhances antitumor responses by targeting regulatory T cells

ABSTRACT: Anti-VEGF treatment enhances antitumor responses by targeting regulatory T cells

PROVIDER: PRJNA1051533 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27185506_1.fastq.gz	Fastqsanger.gz
	SRR27185506_2.fastq.gz	Fastqsanger.gz
	SRR27185507_1.fastq.gz	Fastqsanger.gz
	SRR27185507_2.fastq.gz	Fastqsanger.gz
	SRR27185508_1.fastq.gz	Fastqsanger.gz

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Anti-VEGF treatment enhances antitumor responses by targeting regulatory T cells

Project description:Cholangiocarcinoma (CCA) shows limited response to systemic treatments including immunotherapy. We initiated an open-label phase II clinical trial testing bevacizumab (anti-VEGF-A) plus tremelimumab (anti-CTLA-4) and durvalumab (anti-PD-L1) in patients with primary liver cancer. Exceptional responses were observed in patients with CCA that were accompanied with moderate to severe, yet manageable immune-related events in the majority of patients. Correlative studies using paired PBMC and serum samples demonstrated a proinflammatory cytokine profile, reinvigoration of precursor exhausted CD8+ T cells, and expansion of regulatory T cell and non-classical monocyte subsets. We utilized subcutaneous, orthotopic as well as plasmid-induced murine CCA models to better understand how anti-VEGF-A enhances anti-tumor immunity induced by anti-CTLA4 plus anti-PD-L1. We describe a novel multi-modal mechanism of how anti-VEGF-A therapy enhances immune checkpoint inhibitor-induced immune responses. The treatment effect was dependent on an increase in tumor infiltrating B cells and IL-12 causing Treg rewiring towards fragile and unstable states. Using a mouse model that genetically ablates VEGFR2 expression on Tregs, we show that the VEGF /VEGFR2 axis on Tregs contributes to the pro-tumoral function of Tregs and supports tumor progression in a syngeneic CCA model. This study provides clinical evidence that simultaneously targeting three immunosuppressive axes, namely VEGF-A, CTLA-4 and PD-L1, can elicit strong anti-tumor immunity to potentiate CCA regression and merits broader evaluation in other cancers.

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Project description:Chimeric Antigen Receptor (CAR) T cell therapy was adopted as a clinical modality for patients with relapsed/refractory hematological malignancies. Despite the clinical efficacy of CAR-T cell therapy, a considerable fraction of patients still relapses during the first months following CAR-T cell infusion. The limited CAR-T cell efficiency is thought to relate to epigenetic mechanisms involved in T cell suppression and dysfunction. Here, screening of multiple epigenetic inhibitors revealed that targeting PRC2 consistently enhanced the cytotoxic/effector phenotype of CD8 T cells. Notably, PRC2 inhibition promoted the differentiation of GZMB+ effector memory 19BBζ CAR-T cells and enhanced their antitumor activity both in vitro and in vivo. Consistent with their long-lasting antitumor activity, PRC2-inhibited 19BBζ CAR-T cells did not exhibit any signs of dysfunctionality/exhaustion. Furthermore, TCR restimulation along with PRC2 inhibition of patient-derived anti-CD19 CAR-T cells also induced the development of GZMB+ effector memory cells and elicited potent antitumor responses against CD19+ Daudi cells. In line with this, the gene signature derived from in-house PRC2-inhibited 19BBζ CAR-T cells was enriched in tisagenlecleucel (tisa-cel) BBζ CAR-T cell therapy responders with large B-cell lymphoma. Collectively, our results demonstrated that targeting PRC2 may be a promising approach to enhance a functional effector program in CAR-T cells against hematological malignancies.

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Project description:TIGIT is an immune checkpoint receptor expressed on activated and memory T cells, immunosuppressive T regulatory cells, and natural killer (NK) cells. TIGIT has emerged as an attractive target for antitumor therapies, due to its proposed immunosuppressive effects on lymphocyte function and T cell activation. We generated an anti-TIGIT monoclonal antibody (mAb) that binds with high affinity to human, non-human primate, and murine TIGIT and through multiple experimental methodologies demonstrated that checkpoint blockade alone is insufficient for antitumor activity. Generating anti-TIGIT mAbs with various Fc backbones we show that muting the Fc-Fcγ receptor (FcγR) interaction failed to drive antitumor activity, while mAbs with Fc functional backbones demonstrate substantial antitumor activity, mediated through activation of antigen-presenting cells (APCs), T cell priming, and NK-mediated depletion of suppressive Tregs and exhausted T cells. Further, nonfucosylation of the Fc backbone resulted in enhanced immune responses and antitumor activity relative to the intact IgG1 backbone. The improved activity correlated with the biased FcγR interaction profile of the nonfucosylated anti-TIGIT mAb, which supports that FcγRIIIa binding with decreased FcγRIIb binding favorably activates APCs and enhances tumor-specific CD8+ T cell responses. The anti-TIGIT mAbs with intact FcγR interacting backbones also demonstrated synergistic enhancement of other standard antitumor treatments, including anti-PD-1 treatment and a model monomethyl auristatin E antibody–drug conjugate. These findings highlight the importance of the anti-TIGIT mAb’s Fc backbone to its antitumor activity and the extent to which this activity can be enhanced through nonfucosylation of the backbone

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