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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.

SUBMITTER: Aguilera TA

PROVIDER: S-EPMC7311370 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Induced Tumor Heterogeneity Reveals Factors Informing Radiation and Immunotherapy Combinations.

Aguilera Todd A TA Elghonaimy Eslam A EA Shehade Hussein H Rafat Marjan M Castellini Laura L Jiang Dadi D Kariolis Mihalis M Koong Albert C AC Le Quynh-Thu QT Ellies Lesley G LG Rankin Erinn B EB Graves Edward E EE Giaccia Amato J AJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20200225 12

<h4>Purpose</h4>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.<h4>Experimental design</h4>Evaluate efficacy and immune responses generated by ...[more]

PMID: 32098769

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Project description:BackgroundGlioblastoma (GBM) is a fatal brain tumor with no effective treatment. The specific GBM tumor immune microenvironment (TIME) may contribute to resistance to immunotherapy, a tumor therapy with great potential. Thus, an in-depth understanding of the characteristics of tumor-infiltrating immune cells is essential for exploring biomarkers in GBM pathogenesis and immunotherapy.MethodsWe estimated the relative abundances of 25 immune cell types in 796 GBM samples using single sample gene set enrichment analysis (ssGSEA). Unsupervised clustering was used to identify different GBM-associated TIME immune cell infiltration (GTMEI) patterns. The GTMEIscore system was constructed with principal component analysis (PCA) to determine the immune infiltration pattern of individual tumors.ResultsWe revealed three distinct GTMEI patterns with different clinical outcomes and modulated biological pathways. We developed a scoring system (GTMEIscore) to determine the immune infiltration pattern of individual tumors. We comprehensively analyzed the genomic characteristics, molecular subtypes and clinicopathological features as well as proteomic, phosphoproteomic, acetylomic, lipidomic and metabolomic properties associated with the GTMEIscore and revealed many novel dysregulated pathways and precise targets in GBM. Moreover, the GTMEIscore accurately quantified the immune status of many other cancer types. Clinically, the GTMEIscore was found to have significant potential therapeutic value for chemotherapy/radiotherapy, immune checkpoint inhibitor (ICI) therapy and targeted therapy.ConclusionsFor the first time, we employed a multilevel and multiplatform strategy to construct a multidimensional molecular map of tumors with different immune infiltration patterns. These results may provide theoretical basises for identifying more effective predictive biomarkers and developing more effective drug combination strategies or novel immunotherapeutic agents for GBM.

Dataset Information

Induced Tumor Heterogeneity Reveals Factors Informing Radiation and Immunotherapy Combinations.

Publications

Induced Tumor Heterogeneity Reveals Factors Informing Radiation and Immunotherapy Combinations.

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