Impact of treatment schedule on the efficacy of cytostatic and immunostimulatory agents

Abstract

Radiation therapy (RT) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors mediate poorly overlapping cytostatic and immunostimulatory effects, suggesting that combinatorial regimens may enable supra-additive tumor control. Our preclinical findings demonstrate that administration schedule stands out as a major determinant of efficacy when RT and CDK4/6 inhibitors are combined for breast cancer therapy.

Keywords: 4T1 cells; MCF7 cells; MPA/DMBA-driven mammary carcinomas; TS/A cells; immune checkpoint inhibitors; targeted anticancer agents.

Figure 1.

Impact of treatment schedule on the efficacy of radiation therapy combined with CDK4/6 inhibitors. a. Palbociclib administration arrests breast cancer (BC) cells in the G₁ phase of the cell cycle, resulting in the generation of at least some radioresistance upon the depletion of cells in G₂/M (a). While palbociclib may per se mediate some immunostimulatory effects, including MHC Class I upregulation and the secretion of type III interferon (IFN), the virtually pure cytostasis imposed by palbociclib may prevent the initiation of optimal anticancer immunity upon irradiation, which is at least partially dependent on immunogenic cell death (ICD) (b). Radiation therapy (RT) blocks BC cells in G₂/M (a), a process that (1) at least in some cells is leaky, meaning that such cells can complete mitosis and resume cycling at G₁, and (2) is associated with at least some degree of ICD-driven immunostimulation coupled to compensatory tumor infiltration by regulatory T (T_REG) cells. In this context, the administration of palbociclibafter RT not only mediates superior cytostasis as it arrests BC cells potentially escaping the RT-induced arrest in G₂/M, but may also boost anticancer immunity elicited by ICD as a consequence of T_REG cell depletion (b). CTL, cytotoxic T lymphocyte; DAMP, damage-associated molecular pattern