tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A. 2019 Dec 30. pii: 201904022. doi: 10.1073/pnas.1904022116. [Epub ahead of print] [h=1]Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.[/h]
Newman JH[SUP]1[/SUP], Chesson CB[SUP]1[/SUP], Herzog NL[SUP]1[/SUP], Bommareddy PK[SUP]1[/SUP], Aspromonte SM[SUP]1[/SUP], Pepe R[SUP]1,[/SUP][SUP]2[/SUP], Estupinian R[SUP]1,[/SUP][SUP]3[/SUP], Aboelatta MM[SUP]1,[/SUP][SUP]4[/SUP], Buddhadev S[SUP]1[/SUP], Tarabichi S[SUP]2[/SUP], Lee M[SUP]2[/SUP], Li S[SUP]1[/SUP], Medina DJ[SUP]1[/SUP], Giurini EF[SUP]3[/SUP], Gupta KH[SUP]3[/SUP], Guevara-Aleman G[SUP]3[/SUP], Rossi M[SUP]3[/SUP], Nowicki C[SUP]3[/SUP], Abed A[SUP]3[/SUP], Goldufsky JW[SUP]3[/SUP], Broucek JR[SUP]3,[/SUP][SUP]5[/SUP], Redondo RE[SUP]3,[/SUP][SUP]6[/SUP], Rotter D[SUP]1[/SUP], Jhawar SR[SUP]1,[/SUP][SUP]7[/SUP], Wang SJ[SUP]1[/SUP], Kohlhapp FJ[SUP]1[/SUP], Kaufman HL[SUP]8,[/SUP][SUP]9[/SUP], Thomas PG[SUP]10,[/SUP][SUP]11[/SUP], Gupta V[SUP]3[/SUP], Kuzel TM[SUP]3[/SUP], Reiser J[SUP]3[/SUP], Paras J[SUP]1[/SUP], Kane MP[SUP]1[/SUP], Singer EA[SUP]1,[/SUP][SUP]2[/SUP], Malhotra J[SUP]1[/SUP], Denzin LK[SUP]12[/SUP], Sant'Angelo DB[SUP]12[/SUP], Rabson AB[SUP]12[/SUP], Lee LY[SUP]2[/SUP], Lasfar A[SUP]1,[/SUP][SUP]13[/SUP], Langenfeld J[SUP]2[/SUP], Schenkel JM[SUP]14,[/SUP][SUP]15[/SUP], Fidler MJ[SUP]3[/SUP], Ruiz ES[SUP]16,[/SUP][SUP]17[/SUP], Marzo AL[SUP]3[/SUP], Rudra JS[SUP]18[/SUP], Silk AW[SUP]17,[/SUP][SUP]19[/SUP], Zloza A[SUP]20,[/SUP][SUP]2,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h] 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.
[h=3]Abstract[/h] 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[SUP]+[/SUP] 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.
[h=4]KEYWORDS:[/h] cancer; flu shot; influenza; intratumoral; vaccine
PMID: 31888983 DOI: 10.1073/pnas.1904022116
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Newman JH[SUP]1[/SUP], Chesson CB[SUP]1[/SUP], Herzog NL[SUP]1[/SUP], Bommareddy PK[SUP]1[/SUP], Aspromonte SM[SUP]1[/SUP], Pepe R[SUP]1,[/SUP][SUP]2[/SUP], Estupinian R[SUP]1,[/SUP][SUP]3[/SUP], Aboelatta MM[SUP]1,[/SUP][SUP]4[/SUP], Buddhadev S[SUP]1[/SUP], Tarabichi S[SUP]2[/SUP], Lee M[SUP]2[/SUP], Li S[SUP]1[/SUP], Medina DJ[SUP]1[/SUP], Giurini EF[SUP]3[/SUP], Gupta KH[SUP]3[/SUP], Guevara-Aleman G[SUP]3[/SUP], Rossi M[SUP]3[/SUP], Nowicki C[SUP]3[/SUP], Abed A[SUP]3[/SUP], Goldufsky JW[SUP]3[/SUP], Broucek JR[SUP]3,[/SUP][SUP]5[/SUP], Redondo RE[SUP]3,[/SUP][SUP]6[/SUP], Rotter D[SUP]1[/SUP], Jhawar SR[SUP]1,[/SUP][SUP]7[/SUP], Wang SJ[SUP]1[/SUP], Kohlhapp FJ[SUP]1[/SUP], Kaufman HL[SUP]8,[/SUP][SUP]9[/SUP], Thomas PG[SUP]10,[/SUP][SUP]11[/SUP], Gupta V[SUP]3[/SUP], Kuzel TM[SUP]3[/SUP], Reiser J[SUP]3[/SUP], Paras J[SUP]1[/SUP], Kane MP[SUP]1[/SUP], Singer EA[SUP]1,[/SUP][SUP]2[/SUP], Malhotra J[SUP]1[/SUP], Denzin LK[SUP]12[/SUP], Sant'Angelo DB[SUP]12[/SUP], Rabson AB[SUP]12[/SUP], Lee LY[SUP]2[/SUP], Lasfar A[SUP]1,[/SUP][SUP]13[/SUP], Langenfeld J[SUP]2[/SUP], Schenkel JM[SUP]14,[/SUP][SUP]15[/SUP], Fidler MJ[SUP]3[/SUP], Ruiz ES[SUP]16,[/SUP][SUP]17[/SUP], Marzo AL[SUP]3[/SUP], Rudra JS[SUP]18[/SUP], Silk AW[SUP]17,[/SUP][SUP]19[/SUP], Zloza A[SUP]20,[/SUP][SUP]2,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h] 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.
[h=3]Abstract[/h] 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[SUP]+[/SUP] 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.
[h=4]KEYWORDS:[/h] cancer; flu shot; influenza; intratumoral; vaccine
PMID: 31888983 DOI: 10.1073/pnas.1904022116
Free full text