Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer

TGF beta is a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. However, the expression of TGF beta and its inhibition within the tumor microenvironment has mainly been investigated in stroma-heavy tumors. Using B16 mouse melanoma and CT26 colon carcinoma as models of stroma-poor tumors, we demonstrate that myeloid/dendritic cells are the main sources of TGF beta 1 and TGF beta 3. Depending on local expression of TGF beta isoforms, isoform specific inhibition of either TGF beta 1 or TGF beta 3 may be effective. The TGF beta signature of CT26 colon carcinoma is defined by TGF beta 1 and TGF beta 1 inhibition results in tumor delay; B16 melanoma has equal expression of both isoforms and inhibition of either TGF beta 1 or TGF beta 3 controls tumor growth. Using T cell functional assays, we show that the mechanism of tumor delay is through and dependent on enhanced CD8(+) T cell function. To overcome the local immunosuppressive environment, we found that combining TGF beta inhibition with immune checkpoint blockade results in improved tumor control. Our data suggest that TGF beta inhibition in stroma poor tumors shifts the local immune environment to favor tumor suppression. Gupta et al. demonstrate that targeting isoform-specific TGF beta leads to an increase in the anti-tumor response when compared to pan-TGF beta inhibition, due to enhanced CD8 T cell function. The authors also report that combining TGF beta inhibition with immune checkpoint blockade results in improved tumor control.

Automated summary

The study highlights the potential of TGF beta as a target in cancer treatment, showing that myeloid/dendritic cells are main sources of TGF beta 1 and TGF beta 3 in stroma-poor tumors. Targeting isoform-specific TGF beta leads to enhanced CD8 T cell function and improved tumor control when compared to pan-TGF beta inhibition. Combining TGF beta inhibition with immune checkpoint blockade results in a more effective tumor control by shifting the local immune environment to favor tumor suppression.