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

被引：144

作者：

Newman, Jenna H. ^{[1
]}

Chesson, C. Brent ^{[1
]}

Herzog, Nora L. ^{[1
]}

Bommareddy, Praveen K. ^{[1
]}

Aspromonte, Salvatore M. ^{[1
]}

Pepe, Russell ^{[1
,2
]}

Estupinian, Ricardo ^{[1
,3
]}

Aboelatta, Mones M. ^{[1
,4
]}

Buddhadev, Stuti ^{[1
]}

Tarabichi, Saeed ^{[2
]}

Lee, Michael ^{[2
]}

Li, Shengguo ^{[1
]}

Medina, Daniel J. ^{[1
]}

Giurini, Eileena F. ^{[3
]}

Gupta, Kajal H. ^{[3
]}

Guevara-Aleman, Gabriel ^{[3
]}

Rossi, Marco ^{[3
]}

Nowicki, Christina ^{[3
]}

Abed, Abdulkareem ^{[3
]}

Goldufsky, Josef W. ^{[3
]}

Broucek, Joseph R. ^{[3
,5
]}

Redondo, Raquel E. ^{[3
,6
]}

Rotter, David ^{[1
]}

Jhawar, Sachin R. ^{[1
,7
]}

Wang, Shang-Jui ^{[1
]}

Kohlhapp, Frederick J. ^{[1
]}

Kaufman, Howard L. ^{[8
,9
]}

Thomas, Paul G. ^{[10
,11
]}

Gupta, Vineet ^{[3
]}

Kuzel, Timothy M. ^{[3
]}

Reiser, Jochen ^{[3
]}

Paras, Joyce ^{[1
]}

Kane, Michael P. ^{[1
]}

Singer, Eric A. ^{[1
,2
]}

Malhotra, Jyoti ^{[1
]}

Denzin, Lisa K. ^{[12
]}

Sant'Angelo, Derek B. ^{[12
]}

Rabson, Arnold B. ^{[12
]}

Lee, Leonard Y. ^{[2
]}

Lasfar, Ahmed ^{[1
,13
]}

Langenfeld, John ^{[2
]}

Schenkel, Jason M. ^{[14
,15
]}

Fidler, Mary Jo ^{[3
]}

Ruiz, Emily S. ^{[16
,17
]}

Marzo, Amanda L. ^{[3
]}

Rudra, Jai S. ^{[18
]}

Silk, Ann W. ^{[19
]}

Zloza, Andrew ^{[1
,2
,3
]}

机构：

[1] Rutgers State Univ, Rutgers Canc Inst New Jersey, New Brunswick, NJ 08901 USA

[2] Rutgers State Univ, Rutgers Robert Wood Johnson Med Sch, Dept Surg, New Brunswick, NJ 08901 USA

[3] Rush Univ, Med Ctr, Sect Hematol Oncol & Cell Therapy, Dept Internal Med, Chicago, IL 60612 USA

[4] Columbia Univ, Irving Med Ctr, Inst Genom Med, New York, NY 10032 USA

[5] Vanderbilt Univ, Med Ctr, Dept Surg, Nashville, TN 37232 USA

[6] Franciscan Hlth, Dept Surg, Munster, IN 46321 USA

[7] Ohio State Univ, Arthur G James Comprehens Canc, Dept Radiat Oncol, Columbus, OH 43210 USA

[8] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA

[9] Replimune Inc, Woburn, MA 01801 USA

[10] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

[11] Univ Tennessee, Hlth Sci Ctr, Integrated Biomed Sci Program, Memphis, TN 38105 USA

[12] Rutgers Robert Wood Johnson Med Sch, Child Hlth Inst New Jersey, New Brunswick, NJ 08901 USA

[13] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Pharmacol & Toxicol, Piscataway, NJ 08854 USA

[14] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[15] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[16] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02130 USA

[17] Harvard Med Sch, Boston, MA 02115 USA

[18] Washington Univ, McKelvey Sch Engn, Dept Biomed Engn, St Louis, MO 63105 USA

[19] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2020年 / 117卷 / 02期

关键词：

influenza; vaccine; cancer; intratumoral; flu shot; T-CELLS; INFLUENZA VACCINE; CLINICAL-RESPONSE; VIRUS-INFECTION; PD-1; MICE; LYMPHOCYTES; TOLERANCE; BLOCKADE; MELANOMA;

D O I：

10.1073/pnas.1904022116

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1119 / 1128

页数：10

共 60 条

[1] PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome [J].

Alsaab, Hashem O. ;

Sau, Samaresh ;

Alzhrani, Rami ;

Tatiparti, Katyayani ;

Bhise, Ketki ;

Kashaw, Sushil K. ;

Iyer, Arun K. .

FRONTIERS IN PHARMACOLOGY, 2017, 8

[2] Dissection of T-cell Antigen Specificity in Human Melanoma [J].

Andersen, Rikke Sick ;

Thrue, Charlotte Albaek ;

Junker, Niels ;

Lyngaa, Rikke ;

Donia, Marco ;

Ellebaek, Eva ;

Svane, Inge Marie ;

Schumacher, Ton N. ;

Straten, Per Thor ;

Hadrup, Sine Reker .

CANCER RESEARCH, 2012, 72 (07) :1642-1650

[3]

[Anonymous], 2011, ANIM RES GUIDE CARE

[4]

[Anonymous], 1909, Mr J WARRINGTON HAWARD, DOI [10.1177/003591571000301601, DOI 10.1177/003591571000301601]

[5] IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade [J].

Ayers, Mark ;

Lunceford, Jared ;

Nebozhyn, Michael ;

Murphy, Erin ;

Loboda, Andrey ;

Kaufman, David R. ;

Albright, Andrew ;

Cheng, Jonathan D. ;

Kang, S. Peter ;

Shankaran, Veena ;

Piha-Paul, Sarina A. ;

Yearley, Jennifer ;

Seiwert, Tanguy Y. ;

Ribas, Antoni ;

McClanahan, Terrill K. .

JOURNAL OF CLINICAL INVESTIGATION, 2017, 127 (08) :2930-2940

[6] Understanding the tumor immune microenvironment (TIME) for effective therapy [J].

Binnewies, Mikhail ;

Roberts, Edward W. ;

Kersten, Kelly ;

Chan, Vincent ;

Fearon, Douglas F. ;

Merad, Miriam ;

Coussens, Lisa M. ;

Gabrilovich, Dmitry I. ;

Ostrand-Rosenberg, Suzanne ;

Hedrick, Catherine C. ;

Vonderheide, Robert H. ;

Pittet, Mikael J. ;

Jain, Rakesh K. ;

Zou, Weiping ;

Howcroft, T. Kevin ;

Woodhouse, Elisa C. ;

Weinberg, Robert A. ;

Krummel, Matthew F. .

NATURE MEDICINE, 2018, 24 (05) :541-550

[7] Learning from PD-1 Resistance: New Combination Strategies [J].

Bu, Xia ;

Mahoney, Kathleen M. ;

Freeman, Gordon J. .

TRENDS IN MOLECULAR MEDICINE, 2016, 22 (06) :448-451

[8]

Centers for Disease Control and Prevention (CDC), EST INFL VACC COV AD

[9] Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy [J].

Cristescu, Razvan ;

Mogg, Robin ;

Ayers, Mark ;

Albright, Andrew ;

Murphy, Erin ;

Yearley, Jennifer ;

Sher, Xinwei ;

Liu, Xiao Qiao ;

Lu, Hongchao ;

Nebozhyn, Michael ;

Zhang, Chunsheng ;

Lunceford, Jared ;

Joe, Andrew ;

Cheng, Jonathan ;

Webber, Andrea L. ;

Ibrahim, Nageatte ;

Plimack, Elizabeth R. ;

Ott, Patrick A. ;

Seiwert, Tanguy ;

Ribas, Antoni ;

McClanahan, Terrill K. ;

Tomassini, Joanne E. ;

Loboda, Andrey ;

Kaufman, David .

SCIENCE, 2018, 362 (6411) :197-+

[10] Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells [J].

Dai, Peihong ;

Wang, Weiyi ;

Yang, Ning ;

Serna-Tamayo, Cristian ;

Ricca, Jacob M. ;

Zamarin, Dmitriy ;

Shuman, Stewart ;

Merghoub, Taha ;

Wolchok, Jedd D. ;

Deng, Liang .

SCIENCE IMMUNOLOGY, 2017, 2 (11)

← 1 2 3 4 5 6 →