. 2021 Dec; 9(12):.
doi: 10.3390/vaccines9121392.

Directing T-Cell Immune Responses for Cancer Vaccination and Immunotherapy

Peter Lawrence Smith 1 Katarzyna Piadel 1 Angus George Dalgleish 1 
  • PMID: 34960140
  •     239 References
  •     1 citations


Cancer vaccination and immunotherapy revolutionised the treatment of cancer, a result of decades of research into the immune system in health and disease. However, despite recent breakthroughs in treating otherwise terminal cancer, only a minority of patients respond to cancer immunotherapy and some cancers are largely refractive to immunotherapy treatment. This is due to numerous issues intrinsic to the tumour, its microenvironment, or the immune system. CD4+ and CD8+ αβ T-cells emerged as the primary effector cells of the anti-tumour immune response but their function in cancer patients is often compromised. This review details the mechanisms by which T-cell responses are hindered in the setting of cancer and refractive to immunotherapy, and details many of the approaches under investigation to direct T-cell function and improve the efficacy of cancer vaccination and immunotherapy.

Keywords: T-cell; cancer; checkpoint inhibition; immunotherapy; metabolism; microbiome; vaccine.

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Nat Immunol, 2020 Oct 07; 21(12). PMID: 33020660
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J Immunol, 2014 Jun 20; 193(2). PMID: 24943214
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Xuefang Tan, Jamie L Sande, +2 authors, Philip D Greenberg.
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Vitamin D and human health: lessons from vitamin D receptor null mice.
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Valérie Ostiguy, Eve-Line Allard, +2 authors, Nathalie Labrecque.
J Leukoc Biol, 2007 Jun 08; 82(3). PMID: 17554014
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Int Immunopharmacol, 2010 Sep 16; 10(12). PMID: 20840838
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Michael D Buck, David O'Sullivan, +16 authors, Erika L Pearce.
Cell, 2016 Jun 14; 166(1). PMID: 27293185    Free PMC article.
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Front Immunol, 2018 Jul 25; 9. PMID: 30038619    Free PMC article.
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Nat Immunol, 2017 Oct 24; 18(12). PMID: 29058703
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OX40 is a potent immune-stimulating target in late-stage cancer patients.
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Mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2-dependent pathways are essential for CD8+ T cell-mediated airway hyperresponsiveness and inflammation.
Hiroshi Ohnishi, Katsuyuki Takeda, +5 authors, Erwin W Gelfand.
J Allergy Clin Immunol, 2009 Jan 10; 123(1). PMID: 19130938
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J Immunol, 2012 Jul 17; 189(4). PMID: 22798681
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IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity.
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Immunity, 2019 Jul 06; 51(2). PMID: 31272808
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IL15 Agonists Overcome the Immunosuppressive Effects of MEK Inhibitors.
Michael J Allegrezza, Melanie R Rutkowski, +11 authors, Jose R Conejo-Garcia.
Cancer Res, 2016 Mar 17; 76(9). PMID: 26980764    Free PMC article.
CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help.
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Nat Med, 1999 May 06; 5(5). PMID: 10229232
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Age-related loss of naïve T cells and dysregulation of T-cell/B-cell interactions in human lymph nodes.
Lutfan Lazuardi, Brigitte Jenewein, +3 authors, Beatrix Grubeck-Loebenstein.
Immunology, 2004 Dec 21; 114(1). PMID: 15606793    Free PMC article.
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.
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Memory T cells: strategies for optimizing tumor immunotherapy.
Qingjun Liu, Zhongjie Sun, Ligong Chen.
Protein Cell, 2020 Mar 30; 11(8). PMID: 32221812    Free PMC article.
The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction.
Nicole E Scharping, Ashley V Menk, +5 authors, Greg M Delgoffe.
Immunity, 2016 Aug 09; 45(2). PMID: 27496732    Free PMC article.
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Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8(+) T Cell-Mediated Immunity in Colorectal Cancer.
Nupur Bhattacharya, Robert Yuan, +14 authors, Edgar G Engleman.
Immunity, 2016 Sep 04; 45(3). PMID: 27590114    Free PMC article.
Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.
Kristen E Pauken, Morgan A Sammons, +16 authors, E John Wherry.
Science, 2016 Oct 30; 354(6316). PMID: 27789795    Free PMC article.
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Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy.
Rafael Cubas, Zia Khan, +7 authors, Andrew C Chan.
J Immunother Cancer, 2020 Nov 01; 8(2). PMID: 33127657    Free PMC article.
Activation of p38 mitogen-activated protein kinase is critical step for acquisition of effector function in cytokine-activated T cells, but acts as a negative regulator in T cells activated through the T-cell receptor.
Ching Li, Paul Beavis, +3 authors, Fionula M Brennan.
Immunology, 2010 Sep 30; 132(1). PMID: 20875074    Free PMC article.
Interleukin-21 has activity in patients with metastatic melanoma: a phase II study.
Teresa M Petrella, Richard Tozer, +10 authors, Elizabeth A Eisenhauer.
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mTORC1 and mTORC2 selectively regulate CD8⁺ T cell differentiation.
Kristen N Pollizzi, Chirag H Patel, +5 authors, Jonathan D Powell.
J Clin Invest, 2015 Apr 22; 125(5). PMID: 25893604    Free PMC article.
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Using CRISPR to enhance T cell effector function for therapeutic applications.
Julian J Freen-van Heeren.
Cytokine X, 2021 Feb 20; 3(1). PMID: 33604565    Free PMC article.
Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study.
David F McDermott, Jeffrey A Sosman, +11 authors, Thomas Powles.
J Clin Oncol, 2016 Jan 13; 34(8). PMID: 26755520
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The flagellin of candidate live biotherapeutic Enterococcus gallinarum MRx0518 is a potent immunostimulant.
Delphine L Lauté-Caly, Emma J Raftis, +7 authors, Imke E Mulder.
Sci Rep, 2019 Jan 30; 9(1). PMID: 30692549    Free PMC article.
Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC.
Kwan Ho Tang, Shuai Li, +15 authors, Benjamin G Neel.
Cancer Discov, 2021 Aug 07; 12(1). PMID: 34353854    Free PMC article.
ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients.
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Ann Oncol, 2015 Apr 09; 26(7). PMID: 25851629
Cyp26b1 regulates retinoic acid-dependent signals in T cells and its expression is inhibited by transforming growth factor-β.
Hajime Takeuchi, Aya Yokota, Yoshiharu Ohoka, Makoto Iwata.
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Variations in vitamin D production could possibly explain the seasonality of childhood respiratory infections in Hawaii.
William B Grant.
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Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists.
Christopher T Petersen, Mojibade Hassan, +9 authors, Edmund K Waller.
Blood Adv, 2018 Feb 02; 2(3). PMID: 29386194    Free PMC article.
Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction.
Tingting Wang, J N Rashida Gnanaprakasam, +20 authors, Ruoning Wang.
Nat Metab, 2020 Jul 23; 2(7). PMID: 32694789    Free PMC article.
Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab.
Jingjing Liu, Shuang Li, +7 authors, Ying Cheng.
J Clin Lab Anal, 2019 Jul 10; 33(8). PMID: 31282096    Free PMC article.
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Extracellular signal-regulated kinase (ERK) pathway control of CD8+ T cell differentiation.
Marcos P Damasio, Julia M Marchingo, +3 authors, Andrew J M Howden.
Biochem J, 2020 Dec 12; 478(1). PMID: 33305809    Free PMC article.
Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation.
Khashayar Esfahani, Tho-Alfakar Al-Aubodah, +9 authors, Wilson H Miller.
Nat Commun, 2019 Oct 19; 10(1). PMID: 31624262    Free PMC article.
Systemic immune-inflammation index, SII, for prognosis of elderly patients with newly diagnosed tumors.
Chan Li, Wei Tian, +5 authors, Ke Xie.
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Advances in the Immunomodulatory Properties of Glycoantigens in Cancer.
Valeria da Costa, Teresa Freire.
Cancers (Basel), 2022 Apr 24; 14(8). PMID: 35454762    Free PMC article.