An Oncolytic Adenovirus Targeting Transforming Growth Factor β Inhibits Protumorigenic Signals and Produces Immune...

Area of Science:

• Oncolytic virotherapy
• Cancer immunotherapy
• Molecular and Cellular Oncology

Background:

• Transforming growth factor beta (TGFβ) signaling is a key immunosuppressive mechanism in the tumor microenvironment.
• Existing immunotherapies like anti-programmed death-1 (anti-PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) can be limited by TGFβ-mediated immunosuppression.
• There is a need for novel therapeutic strategies to overcome resistance and improve responses to current cancer immunotherapies.

Purpose of the Study:

• To develop a novel oncolytic adenovirus, rAd.sT, encoding a soluble TGFβ receptor II-Fc fusion protein (sTGFβRIIFc).
• To evaluate the therapeutic efficacy and immunomodulatory effects of rAd.sT in preclinical models of breast and renal cancer.
• To assess the potential of rAd.sT as an enhancer for existing immunotherapies, including anti-PD-1 and anti-CTLA-4 treatments.

Main Methods:

• Construction of a telomerase reverse transcriptase promoter-regulated oncolytic adenovirus (rAd.sT) expressing sTGFβRIIFc.
• In vitro assessment of rAd.sT cytotoxicity in breast and renal tumor cells.
• In vivo evaluation of rAd.sT in immunocompetent mouse models (4T1 breast cancer, Renca renal cancer), including assessment of tumor growth, metastasis, immune cell populations, and cytokine profiles.
• Combination therapy studies with rAd.sT and anti-PD-1/anti-CTLA-4 antibodies.

Main Results:

• rAd.sT demonstrated dose-dependent cytotoxicity against tumor cells and inhibited tumor growth and metastasis in vivo.
• rAd.sT modulated the tumor microenvironment by downregulating TGFβ target genes, inhibiting Th2 cytokines, inducing Th1 responses, and enhancing cytotoxic T cell markers (granzyme B, perforin).
• rAd.sT treatment led to increased CD8+ T cells, CD4+ T memory cells, and dendritic cell maturation, while reducing regulatory T cells (Tregs) and myeloid-derived suppressor cells.
• Combination therapy with rAd.sT significantly improved the efficacy of anti-PD-1 and anti-CTLA-4 antibodies in reducing tumor burden and metastasis.
• Analysis of human tumors revealed high expression of TGFβ and its inducible genes, supporting the rationale for targeting TGFβ in these cancers.

Conclusions:

• The engineered oncolytic adenovirus rAd.sT effectively suppresses tumor growth and metastasis by targeting TGFβ signaling and modulating the immune microenvironment.
• rAd.sT exhibits potent immunomodulatory effects, promoting anti-tumor immunity and enhancing the efficacy of checkpoint inhibitor therapies.
• rAd.sT represents a promising therapeutic candidate for enhancing anti-PD-1 and anti-CTLA-4 treatments in breast and kidney cancers.