. 2020 Aug; 11:1633.
doi: 10.3389/fimmu.2020.01633.

Re-education of the Tumor Microenvironment With Targeted Therapies and Immunotherapies

Shin Foong Ngiow 1 Arabella Young 2 
  • PMID: 32849557
  •     181 References
  •     11 citations


The clinical success of cancer immunotherapies targeting PD-1 and CTLA-4 has ignited a substantial research effort to improve our understanding of tumor immunity. Recent studies have revealed that the immune contexture of a tumor influences therapeutic response and survival benefit for cancer patients. Identifying treatment modalities that limit immunosuppression, relieve T cell exhaustion, and potentiate effector functions in the tumor microenvironment (TME) is of much interest. In particular, combinatorial therapeutic approaches that re-educate the TME by limiting the accumulation of immunosuppressive immune cells, such as Foxp3 regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), while promoting CD8+ and CD4+ effector T cell activity is critical. Here, we review key approaches to target these immunosuppressive immune cell subsets and signaling molecules and define the impact of these changes to the tumor milieu. We will highlight the preclinical and clinical evidence for their ability to improve anti-tumor immune responses as well as strategies and challenges for their implementation. Together, this review will provide understanding of therapeutic approaches to efficiently shape the TME and reinvigorate the immune response against cancer.

Keywords: adenosine; immune toxicity; mucosal-associated invariant T (MAIT) cells; natural killer T (NKT) cells; prostaglandin; regulatory T cells (Tregs); transforming growth factor (TGF)β; tumor-associated myeloid cells.

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Cancer Immunol Res, 2017 Aug 30; 5(9). PMID: 28848055
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Rajani Ravi, Kimberly A Noonan, +13 authors, Atul Bedi.
Nat Commun, 2018 Feb 23; 9(1). PMID: 29467463    Free PMC article.
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V Gopalakrishnan, C N Spencer, +67 authors, J A Wargo.
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Christina Twyman-Saint Victor, Andrew J Rech, +22 authors, Andy J Minn.
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Loise M Francisco, Peter T Sage, Arlene H Sharpe.
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Cancer Cell, 2015 Sep 17; 28(3). PMID: 26373277
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Siqi Chen, Jie Fan, +10 authors, Bin Zhang.
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Nat Immunol, 2018 Jan 20; 19(2). PMID: 29348500    Free PMC article.
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Barbara Maier, Andrew M Leader, +20 authors, Miriam Merad.
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Kaori Sakuishi, Shin Foong Ngiow, +4 authors, Ana C Anderson.
Oncoimmunology, 2013 Jun 05; 2(4). PMID: 23734331    Free PMC article.
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Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells.
Brian Ruffell, Debbie Chang-Strachan, +7 authors, Lisa M Coussens.
Cancer Cell, 2014 Dec 03; 26(5). PMID: 25446896    Free PMC article.
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Rikke B Holmgaard, Dmitriy Zamarin, +2 authors, James P Allison.
J Exp Med, 2013 Jun 12; 210(7). PMID: 23752227    Free PMC article.
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CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade.
Limo Chen, Lixia Diao, +36 authors, Don L Gibbons.
Cancer Discov, 2018 Jul 18; 8(9). PMID: 30012853    Free PMC article.
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The Balancing Act between Cancer Immunity and Autoimmunity in Response to Immunotherapy.
Arabella Young, Zoe Quandt, Jeffrey A Bluestone.
Cancer Immunol Res, 2018 Dec 05; 6(12). PMID: 30510057    Free PMC article.
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Hélène Salmon, Juliana Idoyaga, +19 authors, Miriam Merad.
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Constance J Martin, Abhishek Datta, +19 authors, Thomas Schürpf.
Sci Transl Med, 2020 Mar 28; 12(536). PMID: 32213632
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Thomas A Wynn, Ajay Chawla, Jeffrey W Pollard.
Nature, 2013 Apr 27; 496(7446). PMID: 23619691    Free PMC article.
Highly Cited. Review.
Safety and Efficacy of Nivolumab in Combination With Ipilimumab in Metastatic Renal Cell Carcinoma: The CheckMate 016 Study.
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Dale I Godfrey, Jérôme Le Nours, +2 authors, Jamie Rossjohn.
Immunity, 2018 Mar 22; 48(3). PMID: 29562195
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Cancer Immunol Immunother, 2015 Oct 27; 64(12). PMID: 26497850
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Cancer Discov, 2019 Dec 13; 10(1). PMID: 31826876
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Shuhong Qi, Hui Li, +7 authors, Zhihong Zhang.
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Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers.
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Nature, 2014 Apr 04; 509(7500). PMID: 24695216
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T Kawano, J Cui, +9 authors, M Taniguchi.
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Thibault Voron, Orianne Colussi, +15 authors, Magali Terme.
J Exp Med, 2015 Jan 21; 212(2). PMID: 25601652    Free PMC article.
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David R Minor, Igor Puzanov, +2 authors, Axel Hoos.
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Mucosal-Associated Invariant T Cells Display Diminished Effector Capacity in Oesophageal Adenocarcinoma.
Ashanty M Melo, Aisling M O'Brien, +15 authors, Margaret R Dunne.
Front Immunol, 2019 Jul 30; 10. PMID: 31354725    Free PMC article.
Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment.
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High-Throughput Screening of Combinatorial Immunotherapies with Patient-Specific In Silico Models of Metastatic Colorectal Cancer.
Jakob Nikolas Kather, Pornpimol Charoentong, +9 authors, Niels Halama.
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Assessing Immune-Related Adverse Events of Efficacious Combination Immunotherapies in Preclinical Models of Cancer.
Jing Liu, Stephen J Blake, +7 authors, Michele W L Teng.
Cancer Res, 2016 Aug 10; 76(18). PMID: 27503925
Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity.
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A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment.
Arabella Young, Shin Foong Ngiow, +14 authors, Mark J Smyth.
Cancer Res, 2017 Dec 13; 78(4). PMID: 29229601
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Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses.
Kelly D Moynihan, Cary F Opel, +19 authors, Darrell J Irvine.
Nat Med, 2016 Nov 01; 22(12). PMID: 27775706    Free PMC article.
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The regulatory role of invariant NKT cells in tumor immunity.
Rosanna M McEwen-Smith, Mariolina Salio, Vincenzo Cerundolo.
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Highly Cited. Review.
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Santiago Zelenay, Annemarthe G van der Veen, +9 authors, Caetano Reis e Sousa.
Cell, 2015 Sep 08; 162(6). PMID: 26343581    Free PMC article.
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Mei-Ling Chen, Mikaël J Pittet, +4 authors, Khashayarsha Khazaie.
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MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets.
A Kurioka, J E Ussher, +8 authors, P Klenerman.
Mucosal Immunol, 2014 Oct 02; 8(2). PMID: 25269706    Free PMC article.
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Taming the Sentinels: Microbiome-Derived Metabolites and Polarization of T Cells.
Lukasz Wojciech, Kevin S W Tan, Nicholas R J Gascoigne.
Int J Mol Sci, 2020 Oct 23; 21(20). PMID: 33086747    Free PMC article.
The miRNA Content of Exosomes Released from the Glioma Microenvironment Can Affect Malignant Progression.
Federica Caponnetto, Emiliano Dalla, +8 authors, Daniela Cesselli.
Biomedicines, 2020 Dec 09; 8(12). PMID: 33287106    Free PMC article.
Exploring the Emerging Role of the Gut Microbiota and Tumor Microenvironment in Cancer Immunotherapy.
Qin Qiu, Yuqi Lin, +8 authors, Lianxiang Luo.
Front Immunol, 2021 Jan 26; 11. PMID: 33488618    Free PMC article.
Inflammation-Driven Breast Tumor Cell Plasticity: Stemness/EMT, Therapy Resistance and Dormancy.
Tamir Baram, Linor Rubinstein-Achiasaf, Hagar Ben-Yaakov, Adit Ben-Baruch.
Front Oncol, 2021 Feb 16; 10. PMID: 33585241    Free PMC article.
Identification of a ceRNA Network in Lung Adenocarcinoma Based on Integration Analysis of Tumor-Associated Macrophage Signature Genes.
Lei Zhang, Kai Zhang, +7 authors, Jiaxiang Wang.
Front Cell Dev Biol, 2021 Mar 20; 9. PMID: 33738286    Free PMC article.
Leveraging NKG2D Ligands in Immuno-Oncology.
Mercedes Beatriz Fuertes, Carolina Inés Domaica, Norberto Walter Zwirner.
Front Immunol, 2021 Aug 17; 12. PMID: 34394116    Free PMC article.
PD-1-stimulated T cell subsets are transcriptionally and functionally distinct.
Shalom Lerrer, Anna S Tocheva, +2 authors, Adam Mor.
iScience, 2021 Sep 16; 24(9). PMID: 34522863    Free PMC article.
Improving function of cytotoxic T-lymphocytes by transforming growth factor-β inhibitor in oral squamous cell carcinoma.
Yutaro Kondo, Susumu Suzuki, +11 authors, Toru Nagao.
Cancer Sci, 2021 Jul 27; 112(10). PMID: 34309966    Free PMC article.
Challenges and Opportunities for Immunotherapeutic Intervention against Myeloid Immunosuppression in Glioblastoma.
Mark A Exley, Samantha Garcia, +2 authors, David W Andrews.
J Clin Med, 2022 Feb 26; 11(4). PMID: 35207340    Free PMC article.
Discovery and pharmacological characterization of cetrelimab (JNJ-63723283), an anti-programmed cell death protein-1 (PD-1) antibody, in human cancer models.
Nikki DeAngelis, Catherine Ferrante, +13 authors, Raluca I Verona.
Cancer Chemother Pharmacol, 2022 Mar 18; 89(4). PMID: 35298699    Free PMC article.
Polarization of tumor-associated macrophages by TLR7/8 conjugated radiosensitive peptide hydrogel for overcoming tumor radioresistance.
Yumin Zhang, Zujian Feng, +6 authors, Jianfeng Liu.
Bioact Mater, 2022 Apr 08; 16. PMID: 35386314    Free PMC article.