Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

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Proc Natl Acad Sci U S A. 2019 Dec 30. pii: 201904022. doi: 10.1073/pnas.1904022116. [Epub ahead of print] Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.

Newman JH¹, Chesson CB¹, Herzog NL¹, Bommareddy PK¹, Aspromonte SM¹, Pepe R^1,2, Estupinian R^1,3, Aboelatta MM^1,4, Buddhadev S¹, Tarabichi S², Lee M², Li S¹, Medina DJ¹, Giurini EF³, Gupta KH³, Guevara-Aleman G³, Rossi M³, Nowicki C³, Abed A³, Goldufsky JW³, Broucek JR^3,5, Redondo RE^3,6, Rotter D¹, Jhawar SR^1,7, Wang SJ¹, Kohlhapp FJ¹, Kaufman HL^8,9, Thomas PG^10,11, Gupta V³, Kuzel TM³, Reiser J³, Paras J¹, Kane MP¹, Singer EA^1,2, Malhotra J¹, Denzin LK¹², Sant'Angelo DB¹², Rabson AB¹², Lee LY², Lasfar A^1,13, Langenfeld J², Schenkel JM^14,15, Fidler MJ³, Ruiz ES^16,17, Marzo AL³, Rudra JS¹⁸, Silk AW^17,19, Zloza A^20,2,3.
Author information

1 Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. 2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. 3 Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. 4 Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032. 5 Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232. 6 Department of Surgery, Franciscan Health, Munster, IN 46321. 7 Department of Radiation Oncology, Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210. 8 Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA 02114. 9 Replimune, Inc., Woburn, MA 01801. 10 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105. 11 Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38105. 12 Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901. 13 Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854. 14 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. 15 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115. 16 Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02130. 17 Harvard Medical School, Boston, MA 02115. 18 Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in Saint Louis, Saint Louis, MO 63105. 19 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. 20 Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901; Andrew_Zloza@rush.edu.

Abstract

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8⁺ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.
Copyright ? 2019 the Author(s). Published by PNAS.


KEYWORDS:

cancer; flu shot; influenza; intratumoral; vaccine

PMID: 31888983 DOI: 10.1073/pnas.1904022116
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