Induced tumor heterogeneity reveals factors informing radiation and immunotherapy combinations

Todd A. Aguilera, Eslam A. Elghonaimy, Hussein Shehade, Marjan Rafat, Laura Castellini, Dadi Jiang, Mihalis Kariolis, Albert C. Koong, Quynh Thu Le, Lesley G. Ellies, Erinn B. Rankin, Edward E. Graves, Amato J. Giaccia

Research output: Contribution to journalArticle

Abstract

Purpose: To investigate how induced tumor heterogeneity influences immune responses to radiotherapy 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 radiotherapy could nominate immune active therapies to enhance immune responses after radiotherapy. Experimental Design: Evaluate efficacy and immune responses generated by radiotherapy 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 radiotherapy and evaluate the combination. Results: The addition of the responsive cells to unresponsive tumors led to a greater than expected therapeutic response to radiotherapy 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 radiotherapy. Because differences in matrix components, cell adhesion biology, and innate immune signaling correlated with myeloid cell response and phenotype, we hypothesized that radiotherapy combined with CD40 agonist antibody would sensitize unresponsive tumors. The combination therapy resulted in improved innate and adaptive immune response. Importantly, CD40 treatment increased tumor response to radiotherapy and protected against metastatic spread in a metastatic model. Conclusions: These data combined with transcriptomics from human patients support radiotherapy and myeloid cell targeting for immunologically cold tumors. The established study model presents opportunities to investigate the complex overlapping biologic mechanisms that limit immunotherapy and to implement radiotherapy with different immunotherapy combinations.

Original languageEnglish (US)
Pages (from-to)2972-2985
Number of pages14
JournalClinical Cancer Research
Volume26
Issue number12
DOIs
StatePublished - Jun 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Aguilera, T. A., Elghonaimy, E. A., Shehade, H., Rafat, M., Castellini, L., Jiang, D., Kariolis, M., Koong, A. C., Le, Q. T., Ellies, L. G., Rankin, E. B., Graves, E. E., & Giaccia, A. J. (2020). Induced tumor heterogeneity reveals factors informing radiation and immunotherapy combinations. Clinical Cancer Research, 26(12), 2972-2985. https://doi.org/10.1158/1078-0432.CCR-19-4220