Assessment of the impact of low dose solid tumor irradiation on tumor growth, metastases, immune cell activation, and subsequent immunotherapy in a humanized tumor mouse model
Final Report Abstract
Pre-surgical irradiation is not yet established in the treatment settings for breast cancer patients. Nevertheless, transforming immunological rather “cold” breast cancers by neoadjuvant irradiation into their “hot” variants is supposed to elicit an endogenous tumor immune defense and to enhance immunotherapy efficiency. Moreover, this kind of “in-situ vaccination” is expected to entail immunological tumor suppression even at distant sites (abscopal effect). We investigated cellular and immunological effects of sub-lethal, neoadjuvant irradiation in-vitro and in-vivo by implementing subtype-specific humanized tumor mice (HTM) based on subtypespecific breast cancer cells. These mice allowed to study the mechanisms and efficiency of neoadjuvant and tumor-specific 6 Gy irradiation and concurrent anti-PD-L1 treatment under human-like conditions. Similar to the situation in human patients, we observed a gradually increased immunogenicity from the luminal over the HER2-pos. to the triple negative subtypes in HTM detected by immune cell infiltration into the tumor tissue. Anti-PD-L1 therapy divided the HER2-pos. and triple negative group into responder and non-responder, while the luminal treatment group was basically irresponsive. Irradiation alone was effective in the HER2-pos. and luminal subtype-specific HTM and overcame the irresponsiveness in anti-PD-L1 treated HTM. This treatment success went along with a significantly increased T cell proportion and PD-1 expression in the spleen. Overall, the combination therapy triggered the strongest systemic immune cell activation associated with most efficient inhibition of tumor growth in all HTM. This pre-clinical in-vivo analyses based on HTM demonstrates the potential of single low dose and tumor specific irradiation to induce immune responses even in “cold” hormone receptor-pos. tumors. Combination therapy in all subtype-specific HTM was most efficient in reducing tumor growth and in boosting the immune response and turned anti-PD-L1 non-responder mice into responders. The study provides the basis to translate for the these encouraging therapeutic to the clinical application.
Publications
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Advanced Immune Cell Profiling by Multiparameter Flow Cytometry in Humanized Patient-Derived Tumor Mice. Cancers, 14(9), 2214.
Bruss, Christina; Kellner, Kerstin; Ortmann, Olaf; Seitz, Stephan; Brockhoff, Gero; Hutchinson, James A. & Wege, Anja Kathrin
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Deutsche Gesellschaft für Senologie e.V. 42. Jahreskongress: 06. - 08. Juli 2023, ICM Internationales Congress Center München. Neoadjuvant irradiation and immune checkpoint targeting - a promising approach for breast cancer treatment evaluated in humanized tumor mice (HTM).
Anja K. Wege; Christina Bruss; Veruschka Albert; Kerstin Kellner; Olaf Ortmann; Stephan Seitz; Fabian Pohl & Gero Brockhoff
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Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion. Cancers, 15(9), 2615.
Bruss, Christina; Kellner, Kerstin; Albert, Veruschka; Hutchinson, James A.; Seitz, Stephan; Ortmann, Olaf; Brockhoff, Gero & Wege, Anja K.
