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Myeloid cell-based delivery of IFN-γ reprograms leukemia microenvironment and induces anti-tumoral immune responses

ABSTRACT: The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that Interferon-γ (IFNγ) reduced tumor progression in mouse models of B-cell acute lymphoblastic leukemia (B-ALL) and colorectal carcinoma (MC38). Its activity was dependent on the capacity of the immune system to respond to IFNγ and drove counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFNγ delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8+ T lymphocytes. The activity of IFNγ was further enhanced by either co-delivery of tumor necrosis factor α (TNFα) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE178941 | GEO | 2021/08/23

REPOSITORIES: GEO

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Project description:The roles of V-ATPase subunits in regulating CRC immune evasion remain unclear. By analyzing the Tumor and Immune System Interaction Database (TISIDB) for correlations between V-ATPases subunits and immune activities, we found that subunit ATP6V0A1 was inversely correlated with immune activities, especially with the proportions of effective or memory T cells in colon adenocarcinoma (COAD), suggesting an immunosuppressive role. With Atp6v0a1/ATP6V0A1 knockdown CRC cells and CRC syngeneic and xenograft mouse models, we confirmed that tumor cell-intrinsic ATP6V0A1 promotes the growth of CRC in an immune-dependent manner. To determine the type of immune cells contributing to ATP6V0A1-mediated immune evasion, we used single-cell transcriptome sequencing (sc-RNA seq) to analyze the ATP6V0A1-edited immune microenvironment in murine MC38 tumors. Holistic immune profiles in Atp6v0a1 knockdown and control MC38 tumors were compared. The results showed that Atp6v0a1 interference in MC38 cells increased the percentages of naïve T, effector T, and memory-like T-2 cells in the total T cell population while decreasing the percentages of exhausted T, Treg, and memory-like T-1 cells. Moreover, the percentages of granulocytes, monocytes, and dendritic cells within the myeloid population were increased in Atp6v0a1 knockdown-derived tumors, whereas the percentage of macrophages was decreased. Of all the immune cell subclusters, memory-like T-2 cells exhibited the most significantly increased cell count ratio in shv0a1 tumors vs. control tumors. In addition, memory-like T-2 cells expressed more effector markers than memory-like T-1 cells. These data suggest that MC38-derived ATP6V0A1 induced immunosuppressive tumor microenvironment (TME) and suppression of the effectiveness of memory-like T cells may play important roles in ATP6V0A1-regulated CRC immune evasion. The study provides directions to investigate the roles and mechanisms of ATP6V0A1 regulating anti-tumor immunity and thus shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

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Myeloid cell-based delivery of IFN-γ reprograms leukemia microenvironment and induces anti-tumoral immune responses

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