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An engineered mycobacterium smegmatis expressing anti-PD-L1/IL-15 immunocytokine induces and activates specific antitumor immunity

ABSTRACT: Immune checkpoint inhibitors and cytokines have revolutionized tumor treatment but are still limited by dose-dependent toxicity and efficacy. In situ vaccine platforms based on intelligent microbes are promising therapeutic strategies, which can sustainably deliver drugs locally without causing severe systemic risks. Here, we have innovatively engineered a nonpathogenic, adjuvant-acting Mycobacterium smegmatis (M. smegmatis) that coexpresses a PD-L1 inhibitor and an IL-15 cytokine complex containing the IL-15Rα sushi domain (Ms-PDL1scfv-IL15). We demonstrate that PD-L1 inhibitor and IL-15 secretion systemically binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. The bifunctional Ms-PDL1scfv-IL15 overcomes resistance to PD-L1 blockade, recruits numerous immune cells in situ, induces dendritic cells (DCs) maturation, initiates the M1 anti-tumor polarization of macrophages, increases the proliferation and activation of NK cells and tumor-infiltrating CD8+ T cells, inhibits the Tregs, elicits abscopal effects, stimulates rapid tumor regression, prevents metastasis, and leads to long-term survival in several syngeneic tumor mouse models. We also found that the combination of Ms-PDL1scfv-IL15 with GM–CSF synergistically stunted the tumor progress and stasis. Moreover, intratumoral administration of Ms-PDL1scfv-IL15 can capture tumor antigen fragments, and boost DCs presentation of antigens, which remarkably initiates tumor antigen-specific immune response, leading to durable tumor regression and specific antitumor immunity. In summary, this engineered M. smegmatis to recruit and activate innate and adaptive antitumor immune responses, offering a potent cancer immunotherapy strategy to treat patients with cold tumors or resistance to checkpoint blockade.

ORGANISM(S): Mus musculus

PROVIDER: GSE280146 | GEO | 2024/12/25

REPOSITORIES: GEO

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Project description:Background: The tumor cell-intrinsic function of programmed cell death-ligand 1 (PD-L1) is poorly understood. The roles of the intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression and the response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) were investigated. Methods: Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, ChIP-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells, and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression/or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade. Results: In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched and IL-6 expression was higher in patients with no response to ICI in PD-L1-high NSCLCs. IL-6 expression in PD-L1-high NSCLCs correlated positively with MDSCs and Tregs, but negatively with cytotoxic lymphocytes. In another ICI cohort, a higher baseline serum IL-6 level was associated with poor clinical outcome after ICI therapy. PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting tyrosine phosphatase PTP1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 on the transcription of several cytokines (IL-6, TGFβ, TNFα, IL-1β) and chemokines (CXCL1, CXCL3, CXCL8). PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSC in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing mouse lung tumors were heavily infiltrated by MDSCs with high immunosuppressive function. Treg numbers were increased while the numbers of granzyme B+ or IFNγ+ CD8 T-cells decreased. These responses were shown to be mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B+ or IFNγ+ CD8 T-cells. Conclusions: The tumor-cell-intrinsic function of PD-L1 contributes to immunosuppression and tumor progression by MDSCs through the IL-6/Jak/Stat3 pathway, which may serve as therapeutic target to improve ICI efficacy in patients with PD-L1-high NSCLC.

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An engineered mycobacterium smegmatis expressing anti-PD-L1/IL-15 immunocytokine induces and activates specific antitumor immunity

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