Review
. 2020 Apr; 21(7):.
doi: 10.3390/ijms21072367.

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

Vera Petrova 1 Ihor Arkhypov 1 Rebekka Weber 1 Christopher Groth 1 Peter Altevogt 1 Jochen Utikal 1 Viktor Umansky 1 
Affiliations
  • PMID: 32235439
  •     145 References
  •     14 citations

Abstract

Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance. These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy. New therapeutic approaches targeting other immune checkpoint molecules are also discussed.

Keywords: immune checkpoint inhibitors; immunosuppression; immunotherapy; melanoma; tumor microenvironment.

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Br J Dermatol, 2015 Sep 08; 174(1). PMID: 26343230
The biology and function of fibroblasts in cancer.
Raghu Kalluri.
Nat Rev Cancer, 2016 Aug 24; 16(9). PMID: 27550820
Highly Cited. Review.
Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.
Rodabe N Amaria, Sangeetha M Reddy, +42 authors, Jennifer A Wargo.
Nat Med, 2018 Oct 10; 24(11). PMID: 30297909    Free PMC article.
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iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.
Lesley Seymour, Jan Bogaerts, +16 authors, RECIST working group.
Lancet Oncol, 2017 Mar 09; 18(3). PMID: 28271869    Free PMC article.
Highly Cited. Review.
The immune contexture in human tumours: impact on clinical outcome.
Wolf Herman Fridman, Franck Pagès, Catherine Sautès-Fridman, Jérôme Galon.
Nat Rev Cancer, 2012 Mar 16; 12(4). PMID: 22419253
Highly Cited. Review.
Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression.
Christopher Groth, Xiaoying Hu, +4 authors, Viktor Umansky.
Br J Cancer, 2018 Nov 11; 120(1). PMID: 30413826    Free PMC article.
Highly Cited. Review.
Tadalafil has biologic activity in human melanoma. Results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe).
Jessica C Hassel, Huanhuan Jiang, +10 authors, Viktor Umansky.
Oncoimmunology, 2017 Sep 22; 6(9). PMID: 28932631    Free PMC article.
MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma.
Scott J Rodig, Daniel Gusenleitner, +13 authors, F Stephen Hodi.
Sci Transl Med, 2018 Jul 20; 10(450). PMID: 30021886
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Linking Transcriptomic and Imaging Data Defines Features of a Favorable Tumor Immune Microenvironment and Identifies a Combination Biomarker for Primary Melanoma.
Robyn D Gartrell-Corrado, Andrew X Chen, +14 authors, Yvonne M Saenger.
Cancer Res, 2020 Jan 18; 80(5). PMID: 31948941    Free PMC article.
The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy.
Long Long, Xue Zhang, +4 authors, Honglei Chen.
Genes Cancer, 2019 Jan 04; 9(5-6). PMID: 30603054    Free PMC article.
Highly Cited. Review.
Enhanced IL-34 expression in Nivolumab-resistant metastatic melanoma.
Nanumi Han, Muhammad Baghdadi, +6 authors, Ken-Ichiro Seino.
Inflamm Regen, 2018 Mar 09; 38. PMID: 29515691    Free PMC article.
Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy.
Antoni Ribas, Reinhard Dummer, +17 authors, Georgina V Long.
Cell, 2017 Sep 09; 170(6). PMID: 28886381    Free PMC article.
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Tumor infiltrating lymphocytes: The regulator of melanoma evolution.
Mihaela Antohe, Roxana Ioana Nedelcu, +12 authors, Gabriela Turcu.
Oncol Lett, 2019 Apr 05; 17(5). PMID: 30944610    Free PMC article.
Review.
Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation.
Ana C Anderson, Nicole Joller, Vijay K Kuchroo.
Immunity, 2016 May 19; 44(5). PMID: 27192565    Free PMC article.
Highly Cited. Review.
A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression.
Kathleen M Mahoney, Sachet A Shukla, +14 authors, Gordon J Freeman.
Cancer Immunol Immunother, 2018 Dec 20; 68(3). PMID: 30564891    Free PMC article.
Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3+ Regulatory T Cells (Tregs) in Human Cancers.
Anu Sharma, Sumit K Subudhi, +6 authors, Padmanee Sharma.
Clin Cancer Res, 2018 Jul 29; 25(4). PMID: 30054281    Free PMC article.
Highly Cited.
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.
FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma.
A C Tan, L Emmett, +6 authors, A M Menzies.
Ann Oncol, 2018 Aug 24; 29(10). PMID: 30137228
Myeloid-derived suppressor cells coming of age.
Filippo Veglia, Michela Perego, Dmitry Gabrilovich.
Nat Immunol, 2018 Jan 20; 19(2). PMID: 29348500    Free PMC article.
Highly Cited. Review.
Melanoma induces immunosuppression by up-regulating FOXP3(+) regulatory T cells.
Joel Baumgartner, Cara Wilson, +3 authors, Martin McCarter.
J Surg Res, 2007 Jun 19; 141(1). PMID: 17574040    Free PMC article.
Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards.
Vincenzo Bronte, Sven Brandau, +12 authors, Dmitry I Gabrilovich.
Nat Commun, 2016 Jul 07; 7. PMID: 27381735    Free PMC article.
Highly Cited. Review.
The concept of immune surveillance against tumors. The first theories.
Domenico Ribatti.
Oncotarget, 2016 Oct 21; 8(4). PMID: 27764780    Free PMC article.
Highly Cited. Review.
Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody.
Danbee Ha, Atsushi Tanaka, +10 authors, Shimon Sakaguchi.
Proc Natl Acad Sci U S A, 2018 Dec 28; 116(2). PMID: 30587582    Free PMC article.
Fibroblast-mediated drug resistance in cancer.
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Biochem Pharmacol, 2013 Feb 05; 85(8). PMID: 23376122
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Pembrolizumab versus Ipilimumab in Advanced Melanoma.
Caroline Robert, Jacob Schachter, +20 authors, KEYNOTE-006 investigators.
N Engl J Med, 2015 Apr 22; 372(26). PMID: 25891173
Highly Cited.
Prediction of Response to Immune Checkpoint Inhibitor Therapy Using Early-Time-Point 18F-FDG PET/CT Imaging in Patients with Advanced Melanoma.
Steve Y Cho, Evan J Lipson, +7 authors, Richard L Wahl.
J Nucl Med, 2017 Apr 01; 58(9). PMID: 28360208    Free PMC article.
Highly Cited.
Engineering Nanoparticles for Targeted Remodeling of the Tumor Microenvironment to Improve Cancer Immunotherapy.
Shan Gao, Dongjuan Yang, +6 authors, Kai Shi.
Theranostics, 2019 Jan 22; 9(1). PMID: 30662558    Free PMC article.
Highly Cited. Review.
Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.
Laurent Monney, Catherine A Sabatos, +9 authors, Vijay K Kuchroo.
Nature, 2002 Feb 02; 415(6871). PMID: 11823861
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Mechanisms of checkpoint inhibition-induced adverse events.
P Urwyler, I Earnshaw, +9 authors, S Papa.
Clin Exp Immunol, 2020 Jan 29; 200(2). PMID: 31989585    Free PMC article.
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The role of tumor microenvironment in melanoma therapy resistance.
Rajasekharan Somasundaram, Meenhard Herlyn, Stephan N Wagner.
Melanoma Manag, 2016 Mar 01; 3(1). PMID: 30190870    Free PMC article.
Review.
Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma.
Naoya Yamazaki, Yoshio Kiyohara, +11 authors, Hideaki Tahara.
Cancer Sci, 2017 Mar 08; 108(5). PMID: 28266140    Free PMC article.
Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies.
Spencer C Wei, Nana-Ama A S Anang, +8 authors, James P Allison.
Proc Natl Acad Sci U S A, 2019 Oct 23; 116(45). PMID: 31636208    Free PMC article.
Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab.
Richard P Tobin, Kimberly R Jordan, +5 authors, Martin D McCarter.
Int Immunopharmacol, 2018 Aug 20; 63. PMID: 30121453    Free PMC article.
Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
Frank Stephen Hodi, Vanna Chiarion-Sileni, +16 authors, Jedd D Wolchok.
Lancet Oncol, 2018 Oct 27; 19(11). PMID: 30361170
Highly Cited.
Melanoma antigens and related immunological markers.
Jacob Pitcovski, Ehud Shahar, Elina Aizenshtein, Raphael Gorodetsky.
Crit Rev Oncol Hematol, 2017 Jun 13; 115. PMID: 28602168
Review.
Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer.
Chiao-Wen Kang, Avijit Dutta, +8 authors, Chun-Yen Lin.
Sci Rep, 2015 Oct 27; 5. PMID: 26493689    Free PMC article.
Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients.
Ryan J Sullivan, Omid Hamid, +13 authors, Patrick Hwu.
Nat Med, 2019 Jun 07; 25(6). PMID: 31171876
Highly Cited.
Human neutrophils: Their role in cancer and relation to myeloid-derived suppressor cells.
Katrin Moses, Sven Brandau.
Semin Immunol, 2016 Apr 14; 28(2). PMID: 27067179
Highly Cited. Review.
Multiplex quantitative analysis of cancer-associated fibroblasts and immunotherapy outcome in metastatic melanoma.
Pok Fai Wong, Wei Wei, +4 authors, David L Rimm.
J Immunother Cancer, 2019 Jul 25; 7(1). PMID: 31337426    Free PMC article.
Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.
O Hamid, C Robert, +17 authors, A Ribas.
Ann Oncol, 2019 Feb 05; 30(4). PMID: 30715153    Free PMC article.
Highly Cited.
Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory.
Mauro Poggio, Tianyi Hu, +8 authors, Robert Blelloch.
Cell, 2019 Apr 06; 177(2). PMID: 30951669    Free PMC article.
Highly Cited.
Basis of PD1/PD-L1 Therapies.
Barbara Seliger.
J Clin Med, 2019 Dec 11; 8(12). PMID: 31817953    Free PMC article.
Review.
Neutrophils in cancer: neutral no more.
Seth B Coffelt, Max D Wellenstein, Karin E de Visser.
Nat Rev Cancer, 2016 Jun 11; 16(7). PMID: 27282249
Highly Cited. Review.
A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.
Salah-Eddine Bentebibel, Michael E Hurwitz, +14 authors, Adi Diab.
Cancer Discov, 2019 Apr 17; 9(6). PMID: 30988166
Highly Cited.
Pembrolizumab-Induced Sarcoid-Like Reaction: FDG-PET Scan Interpretation in the Era of Immunotherapy.
Shiva Malaty, Craig M Bastian, +2 authors, Wishwdeep Dhillon.
Cureus, 2020 Aug 31; 12(7). PMID: 32864271    Free PMC article.
Myeloid Cell Modulation by Tumor-Derived Extracellular Vesicles.
Ihor Arkhypov, Samantha Lasser, +5 authors, Viktor Umansky.
Int J Mol Sci, 2020 Sep 04; 21(17). PMID: 32878277    Free PMC article.
Review.
Tumor Lysis Syndrome After a Single Dose of Atezolizumab with Nab-Paclitaxel: A Case Report and Review of Literature.
Xavier Carrier, Sumit Gaur, Alexander Philipovskiy.
Am J Case Rep, 2020 Sep 17; 21. PMID: 32934194    Free PMC article.
Review.
The Influence of Tumor Microenvironment on Immune Escape of Melanoma.
Aleksandra Simiczyjew, Ewelina Dratkiewicz, +3 authors, Dorota Nowak.
Int J Mol Sci, 2020 Nov 12; 21(21). PMID: 33171792    Free PMC article.
Review.
Targeting Tumor-Associated Macrophages to Increase the Efficacy of Immune Checkpoint Inhibitors: A Glimpse into Novel Therapeutic Approaches for Metastatic Melanoma.
Claudia Ceci, Maria Grazia Atzori, Pedro Miguel Lacal, Grazia Graziani.
Cancers (Basel), 2020 Nov 21; 12(11). PMID: 33212945    Free PMC article.
Review.
Genomic GLO1 deletion modulates TXNIP expression, glucose metabolism, and redox homeostasis while accelerating human A375 malignant melanoma tumor growth.
Jana Jandova, Georg T Wondrak.
Redox Biol, 2020 Dec 29; 39. PMID: 33360689    Free PMC article.
Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review.
Fulvio Borella, Mario Preti, +9 authors, Leonardo Micheletti.
Int J Mol Sci, 2020 Dec 31; 22(1). PMID: 33375467    Free PMC article.
Review.
The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment.
Maximilian Haist, Henner Stege, Stephan Grabbe, Matthias Bros.
Cancers (Basel), 2021 Jan 13; 13(2). PMID: 33430105    Free PMC article.
Review.
Stromal Cells Present in the Melanoma Niche Affect Tumor Invasiveness and Its Resistance to Therapy.
Justyna Mazurkiewicz, Aleksandra Simiczyjew, +3 authors, Dorota Nowak.
Int J Mol Sci, 2021 Jan 13; 22(2). PMID: 33430277    Free PMC article.
Review.
Current management of melanoma patients with nodal metastases.
Dale Han, Alexander C J van Akkooi, +5 authors, Douglas Reintgen.
Clin Exp Metastasis, 2021 May 08; 39(1). PMID: 33961168    Free PMC article.
Review.
Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients.
Alexandre Gérard, Jerome Doyen, +10 authors, Barbara Seitz-Polski.
J Immunother Cancer, 2021 Jun 06; 9(6). PMID: 34088741    Free PMC article.
Cancer Stemness Associated With Prognosis and the Efficacy of Immunotherapy in Adrenocortical Carcinoma.
Xiaoxi Shi, Yuanlin Liu, +5 authors, Shijie Xin.
Front Oncol, 2021 Aug 10; 11. PMID: 34367952    Free PMC article.
Expression of PD-L1 Is Associated with Inflammatory Microenvironment in Surgical Specimens of Non-Small Cell Lung Cancer.
Ivan Simundza, Dragan Krnic, +6 authors, Merica Glavina Durdov.
J Pers Med, 2021 Aug 28; 11(8). PMID: 34442411    Free PMC article.
Different Susceptibilities of Human Melanoma Cell Lines to G2/M Blockage and Cell Death Activation in Response to the Estrogen Receptor β agonist LY500307.
Giada Pontecorvi, Maria Bellenghi, +5 authors, Rossella Puglisi.
J Cancer, 2022 Apr 05; 13(5). PMID: 35371312    Free PMC article.