Working from human correlates, Newman et al. demonstrated that intratumoral administration of the seasonal flu vaccine reduced tumor growth in mice with B16 melanoma and in NSG mice with patient-derived lung or melanoma xenografts and autologous T cells. The vaccine synergized with PD-L1 blockade even in ICB-resistant tumors. The vaccine increased intratumoral cross-presenting CD8+ DCs, CD8+ T cells, and tumor-specific CD8+ T cells, thus converting the TME from “cold” to “hot”. The antitumor effect was systemic, was dependent on CD8+ T cells, and was not observed with squalene-adjuvanted vaccine nor with intramuscular administration.
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.
Author Info: (1) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (2) Rutgers Cancer Institute of New Jersey, Rutgers, The State Uni
Author Info: (1) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (2) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (3) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (4) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (5) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (6) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (7) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (8) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032. (9) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (10) Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (11) Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (12) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (13) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (14) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (15) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (16) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (17) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (18) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (19) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (20) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (21) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232. (22) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. Department of Surgery, Franciscan Health, Munster, IN 46321. (23) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (24) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. Department of Radiation Oncology, Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210. (25) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (26) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (27) Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA 02114. Replimune, Inc., Woburn, MA 01801. (28) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38105. (29) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (30) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (31) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (32) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (33) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (34) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (35) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (36) Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901. (37) Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901. (38) Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901. (39) Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (40) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854. (41) Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. (42) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115. (43) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (44) Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02130. Harvard Medical School, Boston, MA 02115. (45) Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612. (46) Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in Saint Louis, Saint Louis, MO 63105. (47) Harvard Medical School, Boston, MA 02115. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. (48) Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901; Andrew_Zloza@rush.edu. Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. Department of Internal Medicine, Section of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL 60612.
