Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer

Joyce V. Lee, Filomena Housley, Christina Yau, Rachel Nakagawa, Juliane Winkler, Johanna M. Anttila, Pauliina M. Munne, Mariel Savelius, Kathleen E. Houlahan, Daniel Mark, Golzar Hemmati, Grace A. Hernandez, Yibing Zhang, Susan Samson, Carole Baas, Marleen Kok, Laura J. Esserman, Laura J. ‘t Veer, Hope S. Rugo, Christina Curtis, Juha Klefström, Mehrdad Matloubian () and Andrei Goga ()
Additional contact information
Joyce V. Lee: University of California
Filomena Housley: University of California
Christina Yau: Buck Institute for Research on Aging
Rachel Nakagawa: University of California
Juliane Winkler: University of California
Johanna M. Anttila: University of Helsinki
Pauliina M. Munne: University of Helsinki
Mariel Savelius: University of Helsinki
Kathleen E. Houlahan: Stanford University School of Medicine
Daniel Mark: University of California
Golzar Hemmati: University of California
Grace A. Hernandez: University of California
Yibing Zhang: University of California
Susan Samson: University of California
Carole Baas: Alamo Breast Cancer Foundation
Marleen Kok: Department of Medical Oncology, Netherlands Cancer Institute
Laura J. Esserman: University of California
Laura J. ‘t Veer: University of California
Hope S. Rugo: University of California
Christina Curtis: Stanford University School of Medicine
Juha Klefström: University of Helsinki
Mehrdad Matloubian: University of California
Andrei Goga: University of California

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects are reversible remains poorly understood. Here, we report that TNBCs with elevated MYC expression are resistant to immune checkpoint inhibitor therapy. Using mouse models and patient data, we show that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, mice experience tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and when strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.

Date: 2022
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DOI: 10.1038/s41467-022-31238-y

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