| Abstract |
Background: Transforming growth factor-β (TGFβ) 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, TGFβ also plays multiple roles in normal tissues, particularly during organogenesis, raising toxicity concerns about TGFβ blockade. Dose-limiting cardiovascular toxicity was observed, possibly due to the blockade of all three TGFβ isoforms. The dominant isoform in tumors is TGFβ1, while TGFβ2 and TGFβ3 seem to be more involved in cardiovascular development. Recent data indicated that selective targeting of TGFβ1 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 TGFβ blockade, we developed neutralizing mAbs targeting mature TGFβ1 or TGFβ3, and tested them, in parallel with anti-panTGFβ 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 TGFβ1, but not that of TGFβ3, increased the efficacy of a prophylactic cellular vaccine against colon cancer CT26. This effect was similar to pan-TGFβ 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 TGFβ1-specific mAb as a single agent, while the TGFβ3 mAb was inactive. In this model, the anti-tumor effect of TGFβ1 blockade was tumor intrinsic rather than immune mediated, as it was also observed in T-cell depleted mice. Mechanistically, TGFβ1 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 TGFβ1 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, TGFβ1 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 TGFβ1 with EMT-related genes, these results support the clinical development of TGFβ1-specific mAbs in melanoma.
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| MeSH term(s) |
Animals ; Antibodies, Neutralizing/pharmacology ; Antineoplastic Agents, Immunological/pharmacology ; Cancer Vaccines/immunology ; Cancer Vaccines/pharmacology ; Cell Line, Tumor ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/immunology ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Epithelial-Mesenchymal Transition/drug effects ; Female ; Male ; Melanoma/drug therapy ; Melanoma/immunology ; Melanoma/metabolism ; Melanoma/pathology ; Mice, Inbred BALB C ; Mice, Transgenic ; Skin Neoplasms/drug therapy ; Skin Neoplasms/immunology ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Transforming Growth Factor beta1/antagonists & inhibitors ; Transforming Growth Factor beta1/immunology ; Transforming Growth Factor beta1/metabolism ; Transforming Growth Factor beta3/antagonists & inhibitors ; Transforming Growth Factor beta3/immunology ; Transforming Growth Factor beta3/metabolism ; Tumor Microenvironment ; Mice |
