Single-cell RNA sequencing reveals myeloid and T cell co-stimulation mediated by IL-7 anti-cancer immunotherapy
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ABSTRACT:
PROVIDER: PRJNA844355 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19505741.fastq.gz | Fastqsanger.gz | |||
| SRR19505742.fastq.gz | Fastqsanger.gz | |||
| SRR19505743.fastq.gz | Fastqsanger.gz | |||
| SRR19507943.fastq.gz | Fastqsanger.gz | |||
| SRR19505744.fastq.gz | Fastqsanger.gz |
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Project description:BackgroundImmune checkpoint inhibitors unleash inhibitory signals on T cells conferred by tumors and surrounding stromal cells. Despite the clinical efficacy of checkpoint inhibitors, the lack of target expression and persistence of immunosuppressive cells limit the pervasive effectiveness of the therapy. These limitations may be overcome by alternative approaches that co-stimulate T cells and the immune microenvironment.MethodsWe analyzed single-cell RNA sequencing data from multiple human cancers and a mouse tumor transplant model to discover the pleiotropic expression of the Interleukin 7 (IL-7) receptor on T cells, macrophages, and dendritic cells.ResultsOur experiment on the mouse model demonstrated that recombinant IL-7 therapy induces tumor regression, expansion of effector CD8 T cells, and pro-inflammatory activation of macrophages. Moreover, spatial transcriptomic data support immunostimulatory interactions between macrophages and T cells.ConclusionThese results indicate that IL-7 therapy induces anti-tumor immunity by activating T cells and pro-inflammatory myeloid cells, which may have diverse therapeutic applicability.
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Project description:Immune checkpoint inhibitors unleash inhibitory signals on effector T cells inflicted by tumor and surrounding stromal cells. Despite the great success of PD-1 inhibitors in a fraction of cancer patients, lack of checkpoint molecule expression and persistence of immunosuppressive cells limit the effects of the therapy. To overcome the limitations, combination therapies or direct stimulation of myeloid cells are being investigated. Nonetheless, combination therapies increase the incidence of side effects, and a single agent co-stimulating T cell and myeloid populations might be a better strategy. Exploring single cell RNA sequencing data from multiple human cancers and mouse tumor model, we found pleiotropic expression of interleukin 7 receptor on T cells, macrophages, and dendritic cells. Treatment of recombinant IL7 induced expansion of effector CD8 T cells along with pro-inflammatory activation of macrophages and dendritic cells. Spatial transcriptomic data revealed strengthen of anti-tumoral interactions between macrophages and T cells by IL7 treatment. Altogether, our results suggest that IL7 therapy is applicable to a broad range of cancer patients.
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Project description:IL-2 and IL-21 are closely related cytokines that might have arisen by gene duplication. Both cytokines promote the function of effector CD8+ T cells, but their distinct effects on antigen-driven differentiation of naïve CD8+ T cells into effector CD8+ T cells are not clearly understood. We found that antigen-induced expression of eomesodermin and maturation of naïve CD8+ T cells into granzyme B and CD44 expressing effector CD8+ T cells was enhanced by IL-2, but, unexpectedly, suppressed by IL-21. Furthermore, IL-21 repressed expression of IL-2Ra and inhibited IL-2-mediated acquisition of a cytolytic CD8+ T cell phenotype. Despite its inhibitory effects, IL-21 did not induce anergy, but instead potently enhanced the capacity of cells to mediate tumor regression upon adoptive transfer. In contrast, IL-2, surprisingly, impaired the subsequent anti-tumor function of transferred cells. Gene expression studies revealed a distinct IL-21-program that was characterized phenotypically by increased expression of L-selectin and functionally by enhanced anti-tumor immunity that was not reversed by secondary in vitro stimulation with antigen and IL-2. Thus, the efficacy of CD8+ T cells for adoptive immunotherapy can be influenced by opposing differentiation programs conferred by IL-2 and IL-21, a finding with important implications for the development of cellular cancer therapies. Two-condition experiment: Cytokine-exposed t-cells subsequentially restimulated without cytokine vs. control t-cells without cytokine subsquentially restimulated without cytokine. 3 independent experiments - 1 with experimental RNA labeled with Cy5, control with Cy3, and 2 with dyes-swapped Keywords: Cytokine exposure comparison
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