Combining dual G9a/DNMTs epigenetic inhibition and immunotherapy to treat metastatic melanoma

Description

The persistent high mortality rate in metastatic melanoma is a symptom of its rising incidence and the need for effective therapies. Previous research has held aberrations in epigenetic regulation partially accountable for the onset and progression of melanoma. While ongoing studies are testing epigenetic drugs targeting histone deacetylases (HDACs), we set out to examine the therapeutic potential of simultaneous inhibition of the histone methyltransferase G9a and DNA methyltransferases in the murine MO4 melanoma model.

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.

Periode	11 feb 2021
Evenementstitel	Immunogenomics of Disease: Accelerating to Patient Benefit
Evenementstype	Conference
Mate van erkenning	International