TGF beta 1 neutralization displays therapeutic efficacy through both an immunomodulatory and a non-immune tumor-intrinsic mechanism

Background Transforming growth factor-beta (TGF beta) is emerging as a promising target for cancer therapy, given its ability to promote progression of advanced tumors and to suppress anti-tumor immune responses. However, TGF beta also plays multiple roles in normal tissues, particularly during organogenesis, raising toxicity concerns about TGF beta blockade. Dose-limiting cardiovascular toxicity was observed, possibly due to the blockade of all three TGF beta isoforms. The dominant isoform in tumors is TGF beta 1, while TGF beta 2 and TGF beta 3 seem to be more involved in cardiovascular development. Recent data indicated that selective targeting of TGF beta 1 promoted the efficacy of checkpoint inhibitor anti-PD1 in transplanted preclinical tumor models, without cardiovascular toxicity. Methods To further explore the therapeutic potential of isoform-specific TGF beta blockade, we developed neutralizing mAbs targeting mature TGF beta 1 or TGF beta 3, and tested them, in parallel with anti-panTGF beta mAb 1D11, in two preclinical models: the transplanted colon cancer model CT26, and the autochthonous melanoma model TiRP. Results We observed that the blockade of TGF beta 1, but not that of TGF beta 3, increased the efficacy of a prophylactic cellular vaccine against colon cancer CT26. This effect was similar to pan-TGF beta blockade, and was associated with increased infiltration of activated CD8 T cells in the tumor, and reduced levels of regulatory T cells and myeloid-derived suppressor cells. In contrast, in the autochthonous TiRP melanoma model, we observed therapeutic efficacy of the TGF beta 1-specific mAb as a single agent, while the TGF beta 3 mAb was inactive. In this model, the anti-tumor effect of TGF beta 1 blockade was tumor intrinsic rather than immune mediated, as it was also observed in T-cell depleted mice. Mechanistically, TGF beta 1 blockade increased mouse survival by delaying the phenotype switch, akin to epithelial-to-mesenchymal transition (EMT), which transforms initially pigmented tumors into highly aggressive unpigmented tumors. Conclusions Our results confirm TGF beta 1 as the relevant isoform to target for cancer therapy, not only in combination with checkpoint inhibitors, but also with other immunotherapies such as cancer vaccines. Moreover, TGF beta 1 blockade can also act as a monotherapy, through a tumor-intrinsic effect blocking the EMT-like transition. Because human melanomas that resist therapy often express a gene signature that links TGF beta 1 with EMT-related genes, these results support the clinical development of TGF beta 1-specific mAbs in melanoma.

Automated summary

TGF beta 1 is an important target for cancer therapy, as selective targeting of TGF beta 1 can enhance the efficacy of cancer treatment and avoid cardiovascular toxicity.