Abstract 1443: CHKing melanoma: CHK1 inhibitor +low dose hydroxyurea triggers immunogenic cell death and immunostimulatory cytokine expression to drive an anti-tumor immune response

Abstract

Abstract About half of melanomas respond to immunotherapy, but we currently lack reliable markers to identify likely responders. Therefore, a large number of patients receive this expensive therapy for no benefit. We have previously shown that inhibition of the cell cycle regulator, Checkpoint kinase 1 (CHK1), with subclinical dose of the replication stress inducer hydroxyurea is cytotoxic in a high proportion of melanomas tested. We now report that CHK1 inhibitor + low dose hydroxyurea (LDHU) treatment triggers immunostimulatory cytokine and chemokine expression, and an immunogenic form of cell death. In xenograft models, the drug combination blocks tumor growth for extended periods after the completion of treatment. In syngeneic mouse melanoma models, the drug combination also effectively controls tumor growth and induces regression in a proportion of cases. It also increases immune cell infiltration and activation of a tumor directed cytotoxic T cell response. We also demonstrate that the drug combination does not adversely affect an adaptive immune response or rapidly proliferating human T cells. The mechanism by which drug treatment promotes cytokine expression is unlikely to involve the cGAS-STING signalling pathway which is commonly defective in melanomas. Using two engineered mouse melanoma models we have found that CHK1 inhibitor + LDHU increases cytotoxic CD8+ T cells and NK cell infiltration and activation, but we have also found increased CD4+ Treg tumor infiltration and increased CD8+ T cell PD-1 expression. We have also found increased expression of other immune checkpoint regulators. This indicates a strong anti-tumor immune response is initiated but immune suppression and T cell exhaustion have limited the extent of the response of the tumor infiltrating T cells. However, circulating T cells retained strong anti-tumor activity. The harvested tumors from the drug combination treated mice that do increase in size after treatment show strong evidence of cytotoxic activity. These data provide evidence that CHK1 inhibitors + LDHU is well tolerated and triggers a strong anti-cancer immune response that should combine with immune therapy, although the selection of the target of the immunotherapy will be critical for successfully overcoming the immune suppression triggered. Citation Format: Brian G. Gabrielli, Martina Proctor, Jazmina Gonzalez Cruz, Bijun Zeng, Riccardo Dolcetti, Colm Keane, Nikolas Haass, James Wells. CHKing melanoma: CHK1 inhibitor +low dose hydroxyurea triggers immunogenic cell death and immunostimulatory cytokine expression to drive an anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1443.