| Literature DB >> 35446942 |
Carlos R Gil Del Alcazar1,2,3, Anne Trinh1,2,3, Maša Alečković1,2,3, Ernesto Rojas Jimenez1,2,3, Nicholas W Harper1, Michael U J Oliphant3,4, Shanshan Xie3,4, Ethan D Krop1, Bethlehem Lulseged1, Katherine C Murphy1, Tanya E Keenan1,2,3,5, Eliezer M Van Allen1,2,3,5, Sara M Tolaney1,2,3,5, Gordon J Freeman1,3, Deborah A Dillon6,7, Senthil K Muthuswamy3,4, Kornelia Polyak1,2,3,5,8.
Abstract
Animal models are critical for the preclinical validation of cancer immunotherapies. Unfortunately, mouse breast cancer models do not faithfully reproduce the molecular subtypes and immune environment of the human disease. In particular, there are no good murine models of estrogen receptor-positive (ER+) breast cancer, the predominant subtype in patients. Here, we show that Nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats recapitulate the heterogeneity for mutational profiles, ER expression, and immune evasive mechanisms observed in human breast cancer. We demonstrate the utility of this model for preclinical studies by dissecting mechanisms of response to immunotherapy using combination TGFBR inhibition and PD-L1 blockade. Short-term treatment of early-stage tumors induced durable responses. Gene expression profiling and spatial mapping classified tumors as inflammatory and noninflammatory, and identified IFNγ, T-cell receptor (TCR), and B-cell receptor (BCR) signaling, CD74/MHC II, and epithelium-interacting CD8+ T cells as markers of response, whereas the complement system, M2 macrophage phenotype, and translation in mitochondria were associated with resistance. We found that the expression of CD74 correlated with leukocyte fraction and TCR diversity in human breast cancer. We identified a subset of rat ER+ tumors marked by expression of antigen-processing genes that had an active immune environment and responded to treatment. A gene signature characteristic of these tumors predicted disease-free survival in patients with ER+ Luminal A breast cancer and overall survival in patients with metastatic breast cancer receiving anti-PD-L1 therapy. We demonstrate the usefulness of this preclinical model for immunotherapy and suggest examination to expand immunotherapy to a subset of patients with ER+ disease. See related Spotlight by Roussos Torres, p. 672. ©2022 The Authors; Published by the American Association for Cancer Research.Entities:
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Year: 2022 PMID： 35446942 PMCID： PMC9177779 DOI： 10.1158/2326-6066.CIR-21-0804
Source DB: PubMed Journal: Cancer Immunol Res ISSN： 2326-6066 Impact factor: 12.020