Journal Article
. 2016 Aug; 6:32351.
doi: 10.1038/srep32351.

Forced co-expression of IL-21 and IL-7 in whole-cell cancer vaccines promotes antitumor immunity

Yang-Zhuo Gu 1 Chuan-Wen Fan 2 Ran Lu 3 Bin Shao 1 Ya-Xiong Sang 1 Qiao-Rong Huang 3 Xue Li 3 Wen-Tong Meng 3 Xian-Ming Mo 3 Yu-Quan Wei 1 
Affiliations
  • PMID: 27571893
  •     43 References
  •     7 citations

Abstract

Genetic modification of whole-cell cancer vaccines to augment their efficacies has a history of over two and a half decades. Various genes and gene combinations, targeting different aspects of immune responses have been tested in pursuit of potent adjuvant effects. Here we show that co-expression of two cytokine members of the common cytokine receptor γ-chain family, IL-21 and IL-7, in whole-cell cancer vaccines boosts antitumor immunity in a CD4(+) and CD8(+) T cell-dependent fashion. It also generates effective immune memory. The vaccine-elicited short-term effects positively correlated with enhanced infiltration of CD4(+) and CD8(+) effector T cells, and the long-term effects positively correlated with enhanced infiltration of effector memory T cells, especially CD8(+) effector memory T cells. Preliminary data suggested that the vaccine exhibited good safety profile in murine models. Taken together, the combination of IL-21 and IL-7 possesses potent adjuvant efficacy in whole-cell vaccines. This finding warrants future development of IL-21 and IL-7 co-expressing whole-cell cancer vaccines and their relevant combinatorial regimens.

A lentiviral microRNA-based system for single-copy polymerase II-regulated RNA interference in mammalian cells.
Frank Stegmeier, Guang Hu, +2 authors, Stephen J Elledge.
Proc Natl Acad Sci U S A, 2005 Sep 06; 102(37). PMID: 16141338    Free PMC article.
Highly Cited.
PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.
Michael A Curran, Welby Montalvo, Hideo Yagita, James P Allison.
Proc Natl Acad Sci U S A, 2010 Feb 18; 107(9). PMID: 20160101    Free PMC article.
Highly Cited.
Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection.
Qiang Gao, Shuang-Jian Qiu, +6 authors, Zhao-You Tang.
J Clin Oncol, 2007 Jun 20; 25(18). PMID: 17577038
Highly Cited.
Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy?
Joannes F M Jacobs, Stefan Nierkens, +2 authors, Gosse J Adema.
Lancet Oncol, 2012 Jan 10; 13(1). PMID: 22225723
Review.
Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies.
Marc Pellegrini, Thomas Calzascia, +12 authors, Tak W Mak.
Nat Med, 2009 Apr 28; 15(5). PMID: 19396174
Overexpression of IL-21 promotes massive CD8+ memory T cell accumulation.
Eve-Line Allard, Marie-Pierre Hardy, +4 authors, Nathalie Labrecque.
Eur J Immunol, 2007 Oct 06; 37(11). PMID: 17918202
Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function.
Rong Zeng, Rosanne Spolski, +9 authors, Warren J Leonard.
J Exp Med, 2005 Jan 05; 201(1). PMID: 15630141    Free PMC article.
Highly Cited.
Clinical blockade of PD1 and LAG3--potential mechanisms of action.
Linh T Nguyen, Pamela S Ohashi.
Nat Rev Immunol, 2014 Dec 24; 15(1). PMID: 25534622
Highly Cited. Review.
Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide-based retroviral vector.
Andrea L Szymczak, Creg J Workman, +4 authors, Dario A A Vignali.
Nat Biotechnol, 2004 Apr 06; 22(5). PMID: 15064769
Highly Cited.
Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool.
Fraia Melchionda, Terry J Fry, +3 authors, Crystal L Mackall.
J Clin Invest, 2005 Apr 21; 115(5). PMID: 15841203    Free PMC article.
Harnessing the biology of IL-7 for therapeutic application.
Crystal L Mackall, Terry J Fry, Ronald E Gress.
Nat Rev Immunol, 2011 Apr 22; 11(5). PMID: 21508983    Free PMC article.
Highly Cited. Review.
Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo.
K S Schluns, W C Kieper, S C Jameson, L Lefrançois.
Nat Immunol, 2001 Mar 23; 1(5). PMID: 11062503
Highly Cited.
IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes.
Yongqing Li, Cassian Yee.
Blood, 2007 Oct 09; 111(1). PMID: 17921346    Free PMC article.
Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.
Shimon Sakaguchi.
Annu Rev Immunol, 2004 Mar 23; 22. PMID: 15032588
Highly Cited. Review.
Increased antigen responsiveness of naive CD8 T cells exposed to IL-7 and IL-21 is associated with decreased CD5 expression.
Julien Gagnon, Xi L Chen, +4 authors, Subburaj Ilangumaran.
Immunol Cell Biol, 2010 Jan 13; 88(4). PMID: 20065997
Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation.
Warren J Leonard, Rosanne Spolski.
Nat Rev Immunol, 2005 Sep 03; 5(9). PMID: 16138102
Highly Cited. Review.
Exogenous expression of mouse interferon gamma cDNA in mouse neuroblastoma C1300 cells results in reduced tumorigenicity by augmented anti-tumor immunity.
Y Watanabe, K Kuribayashi, +4 authors, T Sakata.
Proc Natl Acad Sci U S A, 1989 Dec 01; 86(23). PMID: 2512580    Free PMC article.
Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients?
Ekaterina S Jordanova, Arko Gorter, +5 authors, Gert Jan Fleuren.
Clin Cancer Res, 2008 Apr 03; 14(7). PMID: 18381941
IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy.
Christian S Hinrichs, Rosanne Spolski, +7 authors, Nicholas P Restifo.
Blood, 2008 Feb 16; 111(11). PMID: 18276844    Free PMC article.
Highly Cited.
Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity.
G Dranoff, E Jaffee, +7 authors, R C Mulligan.
Proc Natl Acad Sci U S A, 1993 Apr 15; 90(8). PMID: 8097319    Free PMC article.
Highly Cited.
Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival.
Jung-Hyun Park, Qing Yu, +4 authors, Alfred Singer.
Immunity, 2004 Aug 17; 21(2). PMID: 15308108
Highly Cited.
Differential tumor surveillance by natural killer (NK) and NKT cells.
M J Smyth, K Y Thia, +7 authors, D I Godfrey.
J Exp Med, 2000 Feb 24; 191(4). PMID: 10684858    Free PMC article.
Highly Cited.
IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma.
Hak-Ling Ma, Matthew J Whitters, +5 authors, Kyriaki Dunussi-Joannopoulos.
J Immunol, 2003 Jul 09; 171(2). PMID: 12847225
IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21.
Adrianna Moroz, Cheryl Eppolito, +3 authors, Protul A Shrikant.
J Immunol, 2004 Jul 09; 173(2). PMID: 15240677
Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies.
Karl S Peggs, Sergio A Quezada, +2 authors, James P Allison.
J Exp Med, 2009 Jul 08; 206(8). PMID: 19581407    Free PMC article.
Highly Cited.
Tumor protection by IL-7 secreting whole cell vaccine is merely mediated by NK1.1-positive cells.
Caroline Schroten, Reinilde Scheffer, +3 authors, Robert Kraaij.
J Immunother, 2012 Feb 07; 35(2). PMID: 22306900
Stable antibody expression at therapeutic levels using the 2A peptide.
Jianmin Fang, Jing-Jing Qian, +4 authors, Karin Jooss.
Nat Biotechnol, 2005 Apr 19; 23(5). PMID: 15834403
Highly Cited.
IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells.
Shujuan Liu, Gregory Lizée, +4 authors, Patrick Hwu.
Int Immunol, 2007 Sep 28; 19(10). PMID: 17898044
Immunotherapy of neuroblastoma by an Interleukin-21-secreting cell vaccine involves survivin as antigen.
Michela Croce, Raffaella Meazza, +8 authors, Silvano Ferrini.
Cancer Immunol Immunother, 2008 Mar 08; 57(11). PMID: 18324400
Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells.
Sylvain Ladoire, Laurent Arnould, +5 authors, François Ghiringhelli.
Clin Cancer Res, 2008 Apr 17; 14(8). PMID: 18413832
Tolerance and exhaustion: defining mechanisms of T cell dysfunction.
Andrea Schietinger, Philip D Greenberg.
Trends Immunol, 2013 Nov 12; 35(2). PMID: 24210163    Free PMC article.
Highly Cited. Review.
Tumor-specific T-cell memory: clearing the regulatory T-cell hurdle.
Anik L Côté, Edward J Usherwood, Mary Jo Turk.
Cancer Res, 2008 Mar 15; 68(6). PMID: 18339838    Free PMC article.
Review.
IL-7 promotes the transition of CD4 effectors to persistent memory cells.
JiChu Li, Gail Huston, Susan L Swain.
J Exp Med, 2003 Dec 17; 198(12). PMID: 14676295    Free PMC article.
Highly Cited.
New insights into the regulation of T cells by gamma(c) family cytokines.
Yrina Rochman, Rosanne Spolski, Warren J Leonard.
Nat Rev Immunol, 2009 Jun 23; 9(7). PMID: 19543225    Free PMC article.
Highly Cited. Review.
Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation.
A van Elsas, A A Hurwitz, J P Allison.
J Exp Med, 1999 Aug 03; 190(3). PMID: 10430624    Free PMC article.
Highly Cited.
Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer.
Eiichi Sato, Sara H Olson, +15 authors, Kunle Odunsi.
Proc Natl Acad Sci U S A, 2005 Dec 14; 102(51). PMID: 16344461    Free PMC article.
Highly Cited.
The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands.
Audrey L Kinter, Emily J Godbout, +4 authors, Anthony S Fauci.
J Immunol, 2008 Nov 05; 181(10). PMID: 18981091
Highly Cited.
Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study.
P Quaglino, F Marenco, +6 authors, M G Bernengo.
Ann Oncol, 2009 Jul 23; 21(2). PMID: 19622589
Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediated vitiligo.
C Yee, J A Thompson, +7 authors, P D Greenberg.
J Exp Med, 2000 Dec 06; 192(11). PMID: 11104805    Free PMC article.
Murine interleukin-4 displays potent anti-tumor activity in vivo.
R I Tepper, P K Pattengale, P Leder.
Cell, 1989 May 05; 57(3). PMID: 2785856
Highly Cited.
Interleukin-21: a double-edged sword with therapeutic potential.
Rosanne Spolski, Warren J Leonard.
Nat Rev Drug Discov, 2014 Apr 23; 13(5). PMID: 24751819
Highly Cited. Review.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma.
Frank A Sinicrope, Rafaela L Rego, +3 authors, Daniel J Sargent.
Gastroenterology, 2009 Jul 07; 137(4). PMID: 19577568    Free PMC article.
Highly Cited.
Neurons generated from carcinoma stem cells support cancer progression.
Ran Lu, Chuanwen Fan, +14 authors, Xianming Mo.
Signal Transduct Target Ther, 2017 Dec 22; 2. PMID: 29263908    Free PMC article.
Interleukin-7 Resensitizes Non-Small-Cell Lung Cancer to Cisplatin via Inhibition of ABCG2.
Bin Ke, Ting Wei, +5 authors, Lin Shi.
Mediators Inflamm, 2020 Jan 10; 2019. PMID: 31915416    Free PMC article.
Beyond immune checkpoint blockade: emerging immunological strategies.
Shawn P Kubli, Thorsten Berger, +2 authors, Tak W Mak.
Nat Rev Drug Discov, 2021 Mar 10; 20(12). PMID: 33686237
Review.
The Assessment of IL-21 and IL-22 at the mRNA Level in Tumor Tissue and Protein Concentration in Serum and Peritoneal Fluid in Patients with Ovarian Cancer.
Aleksandra Mielczarek-Palacz, Celina Kruszniewska-Rajs, +4 authors, Joanna Magdalena Gola.
J Clin Med, 2021 Jul 25; 10(14). PMID: 34300224    Free PMC article.
Directing T-Cell Immune Responses for Cancer Vaccination and Immunotherapy.
Peter Lawrence Smith, Katarzyna Piadel, Angus George Dalgleish.
Vaccines (Basel), 2021 Dec 29; 9(12). PMID: 34960140    Free PMC article.
Review.
Advancements of Common Gamma-Chain Family Cytokines in Cancer Immunotherapy.
Alexandra A Wolfarth, Swati Dhar, +3 authors, Byung Ha Lee.
Immune Netw, 2022 Mar 17; 22(1). PMID: 35291658    Free PMC article.
Review.
Cancer vaccines as promising immuno-therapeutics: platforms and current progress.
Jian Liu, Minyang Fu, +3 authors, Xiawei Wei.
J Hematol Oncol, 2022 Mar 20; 15(1). PMID: 35303904    Free PMC article.
Review.