Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 27, 2022
- Source ID
- 10.1038/s41467-022-31238-y
Entities
People
- Andrei Goga
- Carole Baas
- Christina Curtis
- Christina Yau
- Daniel Van De Mark
- Filomena Housley
- Golzar Hemmati
- Grace A. Hernandez
- Hope Rugo
- Johanna M. Anttila
- Joyce V. Lee
- Juha Klefström
- Juliane Winkler
- Kathleen E Houlahan
- Laura Esserman
- Laura J. van't Veer
- Mariel Savelius
- Marleen Kok
- Mehrdad Matloubian
- Pauliina M Munne
- Rachel Nakagawa
- Susan Samson
- Yibing Zhang
Organizations
- Congressionally Directed Medical Research Programs
- The Breast Cancer Research Foundation