@article{60fd65fdf684411383f2ddea3a6fc6d1,
title = "Induced tumor heterogeneity reveals factors informing radiation and immunotherapy combinations",
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.",
author = "Aguilera, {Todd A.} and Elghonaimy, {Eslam A.} and Hussein Shehade and Marjan Rafat and Laura Castellini and Dadi Jiang and Mihalis Kariolis and Koong, {Albert C.} and Le, {Quynh Thu} and Ellies, {Lesley G.} and Rankin, {Erinn B.} and Graves, {Edward E.} and Giaccia, {Amato J.}",
note = "Funding Information: We thank the Stanford Shared FACS Facility, the Stanford Human Immune Monitoring Core, the Stanford Protein and Nucleic Acid Facility, and the UT Southwestern Bioinformatics Core Facility and the fellowship program, Min Kim, and Venkat Malladi for use of their facilities and services. We thank Sharon Clarke and Damiana Chiavolini for assistance with editing the manuscript. This work was supported by the ASTRO Resident Seed Grant# RA2014-3 (to T.A. Aguilera); CPRIT first-time tenure track recruitment award #RR170051 (to T.A. Aguilera/E.E. Graves), Ruth L. Kirschstein National Research Service Award PA-14-015 grant# T32 CA 121940 (to T.A. Aguilera/M. Rafat); Katherine McCormick Advanced Postdoctoral Fellowship and NIH grant# K99CA201304 (to M. Rafat); NIH grants CA-67166 and CA-197713, the Silicon Valley Foundation, the Sydney Frank Foundation and the Kimmelman Fund (to A.J. Giaccia); NIH grant K08CA88035 (to L.G. Ellies); and the Blue Dot Fund (to A. Koong). Funding Information: We thank the Stanford Shared FACS Facility, the Stanford Human Immune Monitoring Core, the Stanford Protein and Nucleic Acid Facility, and the UT Southwestern Bioinformatics Core Facility and the fellowship program, Min Kim, and Venkat Malladi for use of their facilities and services. We thank Sharon Clarke and Damiana Chiavolini for assistance with editing the manuscript. This work was supported by the ASTRO Resident Seed Grant# RA2014-3 (to T.A. Aguilera); CPRIT first-time tenure track recruitment award #RR170051 (to T.A. Aguilera/E.E. Graves), Ruth L. Kirschstein National Research Service Award PA-14-015 grant# T32 CA 121940 (to T.A. Aguilera/M. Rafat); Katherine McCormick Advanced Postdoctoral Fellowship and NIH grant# K99CA201304 (to M. Rafat); NIH grants CA-67166 and CA-197713, the Silicon Valley Foundation, the Sydney Frank Foundation and the Kimmelman Fund (to A.J. Giaccia); NIH grant K08CA88035 (to L.G. Ellies); and the Blue Dot Fund (to A. Koong). Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = jun,
day = "15",
doi = "10.1158/1078-0432.CCR-19-4220",
language = "English (US)",
volume = "26",
pages = "2972--2985",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "12",
}