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Combinatorial Immunotherapies Overcome MYC-Driven Immune Evasion

Joyce V. Lee, Filomena Housley, Christina Yau, Daniel Van de Mark, Rachel Nakagawa, Golzar Hemmati, Grace A. Hernandez, Juliane Winkler, Yibing Zhang, Susan Samson, Carole Baas, Laura J. Esserman, Laura J. Van ‘T Veer, Hope S. Rugo, Mehrdad Matloubian, View ORCID ProfileAndrei Goga
doi: https://doi.org/10.1101/2021.05.07.442684
Joyce V. Lee
1Department of Cell and Tissue Biology, University of California; San Francisco, CA
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
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Filomena Housley
1Department of Cell and Tissue Biology, University of California; San Francisco, CA
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
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Christina Yau
3Cancer and Developmental Therapeutics Program, Buck Institute for Research on Aging; Novato, California, USA
4Departments of Pathology and Laboratory Medicine, University of California; San Francisco, California, USA
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Daniel Van de Mark
1Department of Cell and Tissue Biology, University of California; San Francisco, CA
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
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Rachel Nakagawa
1Department of Cell and Tissue Biology, University of California; San Francisco, CA
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
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Golzar Hemmati
1Department of Cell and Tissue Biology, University of California; San Francisco, CA
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
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Grace A. Hernandez
1Department of Cell and Tissue Biology, University of California; San Francisco, CA
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
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Juliane Winkler
1Department of Cell and Tissue Biology, University of California; San Francisco, CA
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
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Yibing Zhang
1Department of Cell and Tissue Biology, University of California; San Francisco, CA
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
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Susan Samson
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
5UCSF Breast Oncology Program/ Breast Science Advocacy Core; San Francisco, California, USA
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Carole Baas
6Alamo Breast Cancer Foundation; San Antonio, Texas, USA
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Laura J. Esserman
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
7Departments of Surgery and Radiology, University of California; San Francisco, California, USA
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Laura J. Van ‘T Veer
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
4Departments of Pathology and Laboratory Medicine, University of California; San Francisco, California, USA
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Hope S. Rugo
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
8Department of Medicine, Division of Hematology/Oncology, University of California; San Francisco, California, USA
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Mehrdad Matloubian
9Department of Medicine, Division of Rheumatology and Rosalind Russell/Ephraim P Engleman Rheumatology Research Center, University of California; San Francisco, California, USA
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  • For correspondence: andrei.goga@ucsf.edu
Andrei Goga
1Department of Cell and Tissue Biology, University of California; San Francisco, CA
2Helen Diller Family Comprehensive Cancer Center, University of California; San Francisco, California, USA
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  • ORCID record for Andrei Goga
  • For correspondence: andrei.goga@ucsf.edu
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Abstract

For many human cancers, including triple negative breast cancer (TNBC), a modest number of patients benefit from immune checkpoint inhibitors, and few experience cancer remission1. Expression of programed death-ligand 1 (PD-L1), tumor immune infiltration, or tumor mutation burden have been widely investigated for predicting cancer immunotherapy response1-5. Whether specific oncogenes diminish response to immunotherapy6-10 and whether these effects are reversible remains poorly understood. We predicted that MYC, an oncogene that is frequently overexpressed11,12 and is associated with worse prognosis12, may predict immunotherapy response in patients with TNBC. Here, we report that MYC-elevated TNBCs are resistant to immune checkpoint inhibitors. Using mouse models of TNBC and patient data we report 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 reduces MYC expression and increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, most mice experience complete tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and if strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Combinatorial Immunotherapies Overcome MYC-Driven Immune Evasion
Joyce V. Lee, Filomena Housley, Christina Yau, Daniel Van de Mark, Rachel Nakagawa, Golzar Hemmati, Grace A. Hernandez, Juliane Winkler, Yibing Zhang, Susan Samson, Carole Baas, Laura J. Esserman, Laura J. Van ‘T Veer, Hope S. Rugo, Mehrdad Matloubian, Andrei Goga
bioRxiv 2021.05.07.442684; doi: https://doi.org/10.1101/2021.05.07.442684
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Combinatorial Immunotherapies Overcome MYC-Driven Immune Evasion
Joyce V. Lee, Filomena Housley, Christina Yau, Daniel Van de Mark, Rachel Nakagawa, Golzar Hemmati, Grace A. Hernandez, Juliane Winkler, Yibing Zhang, Susan Samson, Carole Baas, Laura J. Esserman, Laura J. Van ‘T Veer, Hope S. Rugo, Mehrdad Matloubian, Andrei Goga
bioRxiv 2021.05.07.442684; doi: https://doi.org/10.1101/2021.05.07.442684

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