Induced tumor heterogeneity reveals factors informing radiation and immunotherapy combinations

Induced tumor heterogeneity reveals factors informing radiation and immunotherapy combinations:

Purpose: To investigate how induced tumor heterogeneity influences immune responses to radiotherapy (RT) with different proportions of mixed immune responsive and unresponsive tumor cells in a triple negative breast cancer model. It is hypothesized that studying the immune environment of mixed tumors and responses to RT could nominate immune active therapies to enhance immune responses after RT. Experimental Design: Evaluate efficacy and immune responses generated by RT in tumors with different proportions of immunologically responsive and unresponsive tumor cells. Then study the cellular responses and transcriptomic differences between the tumors to nominate immunotherapy combinations with RT and evaluate the combination. Results: The addition of the responsive cells to unresponsive tumors led to a greater than expected therapeutic response to RT with both innate and adaptive immune components. There was a distinct change in myeloid cells, greater inflammatory macrophage activity, and enhanced antigen presentation with responsive cells after RT. Since differences in matrix components, cell adhesion biology, and innate immune signaling correlated with myeloid cell response and phenotype, we hypothesized that RT combined with CD40 agonist antibody would sensitize unresponsive tumors. The combination therapy resulted improved innate and adaptive immune response. Importantly, CD40 treatment increased tumor response to RT and protected against metastatic spread in a metastatic model. Conclusions: These data combined with transcriptomics from human patients supports RT and myeloid cell targeting for immunologically cold tumors and presents opportunities to investigate the complex overlapping biologic mechanisms that limit immunotherapy and to implement RT with different immunotherapy combinations.