CD8 immunoPET imaging to stratify response and guide combination immunotherapy and radiation in triple negative breast cancer

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PURPOSE: PET imaging targeting immune cells can be used to dynamically monitor intratumoral immune modulation in tissues. Radiation therapy is known to alter the tumor immune microenvironment; therefore, this study demonstrates how CD8 immunoPET imaging can optimize combination immunotherapy and radiation therapy by stratifying tumors who could derive the greatest benefit from immunotherapy following radiation therapy. EXPERIMENTAL DESIGN: A radiation resistant triple negative breast cancer cell line was derived through repeat irradiation of the radiosensitive parental 4T1 cell line prior to in vivo studies, until a radiation resistant subclone (RR-4T1) was isolated. CD8 immunoPET imaging was used to image immune cell infiltration in response to fractionated radiotherapy in radiation sensitive and radiation resistant 4T1 breast cancer models. In this genetically matched radiation sensitive and resistant model, we explore how radiation resistance alters radiation-induced immune modulation and CD8 T cell trafficking with flow cytometry, while response to combination radiation and immunotherapy was assessed in the radiosensitive parental 4T1 model. CD8 immunoPET was utilized to stratify for long-term therapeutic response to immunotherapy based on post-radiation therapy changes in CD8 tissue infiltration. RESULTS: Radiosensitive parental 4T1 tumors show increased CD8 immunoPET signal (SUV) when treated with radiation therapy, relative to control tumors (p < 0.01) whereas radiation resistant 4T1 tumors showed no change following radiation therapy (p = 0.99), which was validated with flow cytometry. When tumors were stratified for high or low CD8 minibody uptake, CD8-high radiosensitive parental 4T1 tumors treated with radiation and immunotherapy had significantly increased sensitivity to immunotherapy compared to CD8-low radiosensitive parental 4T1 tumors (p < 0.05). CONCLUSION: Radiation therapy enhanced CD8 + expression in tumors and CD8 immunoPET effectively stratifies tumors that are more likely to respond to subsequent immunotherapy. CD8 immunoPET provides an approach to optimize combination immunotherapy following radiation treatment in triple-negative breast cancer.

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