Given the expected pleiotropic activity of G9a and DNMTs inhibition, RNA sequencing and Nanostring analysis were first adopted to scout effects of the dual G9a/DNMTs inhibitor CM272 on MO4 tumor cells in vitro and on the tumor in vivo. Significant changes were next validated in vitro. Finally, in vivo anti-tumor effects of CM272 were examined in combination with: (i) dendritic cell vaccination, (ii) adoptive T cell transfer, and (iii) anti-PD-1 immune checkpoint blockade.
We found that CM272 was able to temporarily reduce tumor growth both in vitro and in vivo. RNA sequencing revealed that re-expression of p21 forced tumor cells to arrest in the G1 phase of cell cycle and subsequently undergo apoptosis, along with the induction of DNA damage and a type I interferon response. In vitro, CM272 did not prevent T cell activation or proliferation, and promoted tumor recognition by effector T cells. In vivo, CM272 temporarily delayed tumor growth creating a window-of-opportunity characterized by the induction of an inflammatory response and type I interferon signaling. We found that CM272 and dendritic cell vaccination or adoptive T cell therapy jointly delayed tumor growth thereby prolonging mouse survival.
In conclusion our study underlines the possibility to exploit a dual epigenetic drug targeting G9a and DNMTs against melanoma and combine it with active and adoptive immunotherapy. The drug exerts direct anti-tumor effects, shapes antigenicity and immunogenicity of tumor cells and the tumor immune contexture. As a consequence, the combination with tumor-specific dendritic cell vaccination and tumor-redirected TCR engineered T cell therapy results in cooperative anti-tumor effects. Further research is warranted to fully elucidate the mechanisms of actions and understand whether the approach could be translated to other tumor models.
|Publication status||Unpublished - 2021|
|Event||Immunogenomics of Disease: Accelerating to Patient Benefit - |
Duration: 10 Feb 2021 → 12 Mar 2021
|Conference||Immunogenomics of Disease: Accelerating to Patient Benefit|
|Period||10/02/21 → 12/03/21|