In an effort to develop a new
therapy for
cancer and to improve antiprogrammed death inhibitor-1 (anti-PD-1) and anticytotoxic T lymphocyte-associated
protein (anti-CTLA-4) responses, we have created a
telomerase reverse transcriptase promoter-regulated oncolytic adenovirus rAd.sT containing a soluble
transforming growth factor receptor II fused with human
IgG Fc fragment (sTGFβRIIFc) gene.
Infection of breast and renal
tumor cells with rAd.sT produced sTGFβRIIFc
protein with dose-dependent cytotoxicity. In immunocompetent mouse 4T1
breast tumor model, intratumoral delivery of rAd.sT inhibited both
tumor growth and lung
metastases. rAd.sT downregulated the expression of several
transforming growth factor β (TGFβ) target genes involved in
tumor growth and
metastases, inhibited Th2
cytokine expression, and induced Th1
cytokines and
chemokines, and
granzyme B and
perforin expression. rAd.sT treatment also increased the percentage of CD8+ T lymphocytes, promoted the generation of CD4+ T memory cells, reduced regulatory T lymphocytes (Tregs), and reduced bone marrow-derived suppressor cells. Importantly, rAd.sT treatment increased the percentage of CD4+ T lymphocytes, and promoted differentiation and maturation of
antigen-presenting dendritic cells in the spleen. In the immunocompetent mouse Renca renal
tumor model, similar
therapeutic effects and immune activation results were observed. In the 4T1 mammary
tumor model, rAd.sT improved the inhibition of
tumor growth and lung and liver
metastases by anti-PD-1 and anti-CTLA-4
antibodies. Analysis of the human breast and kidney
tumors showed that a significant number of
tumor tissues expressed high levels of TGFβ and TGFβ-inducible genes. Therefore, rAd.sT could be a potential enhancer of anti-PD-1 and anti-CTLA-4
therapy for treating breast and
kidney cancers.