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Overcoming Immunotherapy Resistance in Breast Cancer Using RT-Mediated Immunomodulation

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[Technical Report, Annual Report]

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Breast cancer generally exhibits low response rates to immunotherapy such as PD-1PD-L1 blockade for multiple reasons including tumor-mediated immune suppression and poor immunogenicity. We sought to change the responsiveness of breast tumors to anti-PD-1 therapy by reshaping the tumor immune microenvironment using focal radiation RT. Irradiation of breast tumors elicits direct killing of malignant cells, but more importantly generates an anti-tumor immune response. This immune reaction is a critical mediator of both primary tumor control and abscopal responses, though the cellular and molecular dynamics within the immune compartment following treatment are incompletely understood. We elucidated these changes using single-cell sequencing in a preclinical model of breast cancer. We found that immediately following RT intratumoral immune cells are largely eliminated and a de novo inflammatory response initiated. The ensuing response consists of activated cytotoxic CD8 T cells and CD11b myeloidmacrophages, but also induced regulatory T cells and inhibitory signals including PD-1 on T cells and PD-L1 on macrophages. We found that RT synergizes with PD-1 blockade through its ability to alleviate intratumoral immunosuppression and stimulate the production of cytotoxic T cells through the generation of a hyperphagocytic, cytotoxic and antigen presenting macrophage phenotype. Examination of biopsies from breast cancer patients undergoing neoadjuvant anti-PD-1 and RT revealed similar changes. We observed enhanced macrophage mediated killing and antigen presentation leading to increased numbers and activation of intratumoral immune responses across more than 80 percent of patients examined. These observations support the notion that RT mediated changes in the tumor immune microenvironment enhance the sensitivity of breast tumors to checkpoint blockade.


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  • Medicine and Medical Research

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[A, Approved For Public Release]