. 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 
  • PMID: 32235439
  •     145 References
  •     14 citations


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.

Subpopulations of myeloid-derived suppressor cells impair T cell responses through independent nitric oxide-related pathways.
Patrick L Raber, Paul Thevenot, +9 authors, Paulo C Rodriguez.
Int J Cancer, 2013 Nov 22; 134(12). PMID: 24259296    Free PMC article.
Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma.
Paolo Antonio Ascierto, Pier Francesco Ferrucci, +16 authors, Antoni Ribas.
Nat Med, 2019 Jun 07; 25(6). PMID: 31171878
Highly Cited.
Moderate physical exercise improves lymphocyte function in melanoma-bearing mice on a high-fat diet.
Cesar Miguel Momesso Dos Santos, Vinicius Leonardo Sousa Diniz, +13 authors, Renata Gorjão.
Nutr Metab (Lond), 2019 Sep 19; 16. PMID: 31528182    Free PMC article.
Melanoma: a prototype of cancer-testis antigen-expressing malignancies.
Sepideh Faramarzi, Soudeh Ghafouri-Fard.
Immunotherapy, 2017 Oct 17; 9(13). PMID: 29032737
Dynamic Changes in PD-L1 Expression and Immune Infiltrates Early During Treatment Predict Response to PD-1 Blockade in Melanoma.
Ricardo E Vilain, Alexander M Menzies, +15 authors, Richard A Scolyer.
Clin Cancer Res, 2017 May 18; 23(17). PMID: 28512174
Highly Cited.
Nanoenabled Modulation of Acidic Tumor Microenvironment Reverses Anergy of Infiltrating T Cells and Potentiates Anti-PD-1 Therapy.
Yu-Xue Zhang, Yang-Yang Zhao, +5 authors, Jun Wang.
Nano Lett, 2019 Apr 04; 19(5). PMID: 30943039
Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion.
Robert D Schreiber, Lloyd J Old, Mark J Smyth.
Science, 2011 Mar 26; 331(6024). PMID: 21436444
Highly Cited. Review.
Anti-PD1 in the wonder-gut-land.
Marie Vetizou, Giorgio Trinchieri.
Cell Res, 2018 Jan 18; 28(3). PMID: 29336431    Free PMC article.
The Immunology of Melanoma.
Jennifer S Ko.
Clin Lab Med, 2017 Aug 15; 37(3). PMID: 28802495
Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma.
Robert H I Andtbacka, Howard L Kaufman, +26 authors, Robert S Coffin.
J Clin Oncol, 2015 May 28; 33(25). PMID: 26014293
Highly Cited.
Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients.
Kimberly R Jordan, Rodabe N Amaria, +6 authors, Martin D McCarter.
Cancer Immunol Immunother, 2013 Sep 28; 62(11). PMID: 24072401    Free PMC article.
Expression of lymphocyte-activating gene 3 and T-cell immunoreceptor with immunoglobulin and ITIM domains in cutaneous melanoma and their correlation with programmed cell death 1 expression in tumor-infiltrating lymphocytes.
Woo Jin Lee, Ye Jin Lee, +5 authors, Sung Eun Chang.
J Am Acad Dermatol, 2019 Mar 19; 81(1). PMID: 30880064
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.
Nadeem Riaz, Jonathan J Havel, +22 authors, Timothy A Chan.
Cell, 2017 Oct 17; 171(4). PMID: 29033130    Free PMC article.
Highly Cited.
Biomarkers for Predicting Efficacies of Anti-PD1 Antibodies.
Yumi Kambayashi, Taku Fujimura, Takanori Hidaka, Setsuya Aiba.
Front Med (Lausanne), 2019 Aug 17; 6. PMID: 31417907    Free PMC article.
IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade.
Mark Ayers, Jared Lunceford, +12 authors, Terrill K McClanahan.
J Clin Invest, 2017 Jun 27; 127(8). PMID: 28650338    Free PMC article.
Highly Cited.
Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function.
Paolo Serafini, Kristen Meckel, +6 authors, Ivan Borrello.
J Exp Med, 2006 Nov 15; 203(12). PMID: 17101732    Free PMC article.
Highly Cited.
No association between prediagnosis exercise and survival in patients with high-risk primary melanoma: A population-based study.
Emily Schwitzer, Irene Orlow, +6 authors, GEM Study Group.
Pigment Cell Melanoma Res, 2017 Apr 12; 30(4). PMID: 28397350    Free PMC article.
Combining radiotherapy and ipilimumab induces clinically relevant radiation-induced abscopal effects in metastatic melanoma patients: A systematic review.
Rodolfo Chicas-Sett, Ignacio Morales-Orue, Delvys Rodriguez-Abreu, Pedro Lara-Jimenez.
Clin Transl Radiat Oncol, 2018 Mar 30; 9. PMID: 29594244    Free PMC article.
The Role of Immune Checkpoint Blockade in Uveal Melanoma.
Anja Wessely, Theresa Steeb, +5 authors, Markus Vincent Heppt.
Int J Mol Sci, 2020 Feb 06; 21(3). PMID: 32013269    Free PMC article.
Cancer immunoediting: from immunosurveillance to tumor escape.
Gavin P Dunn, Allen T Bruce, +2 authors, Robert D Schreiber.
Nat Immunol, 2002 Oct 31; 3(11). PMID: 12407406
Highly Cited. Review.
Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients.
Marine Cordonnier, Charlée Nardin, +6 authors, Jessica Gobbo.
J Extracell Vesicles, 2020 Feb 01; 9(1). PMID: 32002173    Free PMC article.
Impact of radiation, systemic therapy and treatment sequencing on survival of patients with melanoma brain metastases.
Ricarda Rauschenberg, Johannes Bruns, +24 authors, Friedegund Meier.
Eur J Cancer, 2019 Feb 12; 110. PMID: 30739835
Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial.
Georgina V Long, Victoria Atkinson, +21 authors, Matteo S Carlino.
Lancet Oncol, 2017 Jul 22; 18(9). PMID: 28729151
Highly Cited.
Monitoring of patients with metastatic melanoma treated with immune checkpoint inhibitors using PET-CT.
Antonia Dimitrakopoulou-Strauss.
Cancer Immunol Immunother, 2018 Aug 21; 68(5). PMID: 30123922
CD28, CTLA-4 and their ligands: who does what and to whom?
D M Sansom.
Immunology, 2000 Sep 30; 101(2). PMID: 11012769    Free PMC article.
An immunogenic personal neoantigen vaccine for patients with melanoma.
Patrick A Ott, Zhuting Hu, +37 authors, Catherine J Wu.
Nature, 2017 Jul 06; 547(7662). PMID: 28678778    Free PMC article.
Highly Cited.
Recent success and limitations of immune checkpoint inhibitors for cancer: a lesson from melanoma.
Margaret Ottaviano, Sabino De Placido, Paolo Antonio Ascierto.
Virchows Arch, 2019 Feb 13; 474(4). PMID: 30747264
On the Horizon: Targeting Next-Generation Immune Checkpoints for Cancer Treatment.
Grazia R Tundo, Diego Sbardella, +2 authors, Stefano Marini.
Chemotherapy, 2019 Aug 07; 64(2). PMID: 31387102
A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.
Livnat Jerby-Arnon, Parin Shah, +49 authors, Aviv Regev.
Cell, 2018 Nov 06; 175(4). PMID: 30388455    Free PMC article.
Highly Cited.
Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape.
Janis M Taube, Robert A Anders, +8 authors, Lieping Chen.
Sci Transl Med, 2012 Mar 31; 4(127). PMID: 22461641    Free PMC article.
Highly Cited.
Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma.
Antoni Ribas, Donald Lawrence, +14 authors, Omid Hamid.
Nat Med, 2019 Jun 07; 25(6). PMID: 31171879    Free PMC article.
Highly Cited.
Targeted agents and immunotherapies: optimizing outcomes in melanoma.
Jason J Luke, Keith T Flaherty, Antoni Ribas, Georgina V Long.
Nat Rev Clin Oncol, 2017 Apr 05; 14(8). PMID: 28374786
Highly Cited. Review.
Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model.
Alexandra Sevko, Tillmann Michels, +6 authors, Viktor Umansky.
J Immunol, 2013 Jan 30; 190(5). PMID: 23359505    Free PMC article.
Anti-PD-1 and Novel Combinations in the Treatment of Melanoma-An Update.
Frank Friedrich Gellrich, Marc Schmitz, Stefan Beissert, Friedegund Meier.
J Clin Med, 2020 Jan 18; 9(1). PMID: 31947592    Free PMC article.
Metformin: Focus on Melanoma.
Emilie Jaune, Stéphane Rocchi.
Front Endocrinol (Lausanne), 2018 Sep 07; 9. PMID: 30186236    Free PMC article.
Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy.
Tuba N Gide, Camelia Quek, +22 authors, James S Wilmott.
Cancer Cell, 2019 Feb 13; 35(2). PMID: 30753825
Highly Cited.
Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy.
Hui-Ming Chen, Ge Ma, +13 authors, Shu-Hsia Chen.
Clin Cancer Res, 2015 Apr 30; 21(18). PMID: 25922428    Free PMC article.
Cancer Cell Membrane Camouflaged Nanoparticles to Realize Starvation Therapy Together with Checkpoint Blockades for Enhancing Cancer Therapy.
Wei Xie, Wei-Wei Deng, +16 authors, Wei Liu.
ACS Nano, 2019 Feb 26; 13(3). PMID: 30803232
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.
Georgina V Long, Daniil Stroyakovskiy, +31 authors, Keith Flaherty.
Lancet, 2015 Jun 04; 386(9992). PMID: 26037941
Highly Cited.
Myeloid-derived suppressor cells as regulators of the immune system.
Dmitry I Gabrilovich, Srinivas Nagaraj.
Nat Rev Immunol, 2009 Feb 07; 9(3). PMID: 19197294    Free PMC article.
Highly Cited. Review.
Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model.
Christiane Meyer, Alexandra Sevko, +8 authors, Viktor Umansky.
Proc Natl Acad Sci U S A, 2011 Oct 05; 108(41). PMID: 21969559    Free PMC article.
Highly Cited.
Targeting antigen-presenting cells by anti-PD-1 nanoparticles augments antitumor immunity.
Farideh Ordikhani, Mayuko Uehara, +12 authors, Reza Abdi.
JCI Insight, 2018 Oct 20; 3(20). PMID: 30333312    Free PMC article.
Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab.
Jeffrey Weber, Geoffrey Gibney, +11 authors, Yian Ann Chen.
Cancer Immunol Res, 2016 Feb 14; 4(4). PMID: 26873574    Free PMC article.
Highly Cited.
TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients.
Joe-Marc Chauvin, Ornella Pagliano, +8 authors, Hassane M Zarour.
J Clin Invest, 2015 Apr 14; 125(5). PMID: 25866972    Free PMC article.
Highly Cited.
18F-FDG PET/CT for Monitoring of Ipilimumab Therapy in Patients with Metastatic Melanoma.
Kimiteru Ito, Rebecca Teng, +7 authors, Wolfgang A Weber.
J Nucl Med, 2018 Nov 11; 60(3). PMID: 30413661    Free PMC article.
Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma.
Muhammad Zubair Afzal, Rima R Mercado, Keisuke Shirai.
J Immunother Cancer, 2018 Jul 04; 6(1). PMID: 29966520    Free PMC article.
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.
Willy Hugo, Jesse M Zaretsky, +15 authors, Roger S Lo.
Cell, 2016 Mar 22; 165(1). PMID: 26997480    Free PMC article.
Highly Cited.
TIGIT: A Key Inhibitor of the Cancer Immunity Cycle.
Nicholas A Manieri, Eugene Y Chiang, Jane L Grogan.
Trends Immunol, 2016 Oct 30; 38(1). PMID: 27793572
The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells.
Xin Yu, Kristin Harden, +9 authors, Jane L Grogan.
Nat Immunol, 2008 Nov 18; 10(1). PMID: 19011627
Highly Cited.
Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.
Zachary R Chalmers, Caitlin F Connelly, +21 authors, Garrett M Frampton.
Genome Med, 2017 Apr 20; 9(1). PMID: 28420421    Free PMC article.
Highly Cited.
PD-L1:CD80 Cis-Heterodimer Triggers the Co-stimulatory Receptor CD28 While Repressing the Inhibitory PD-1 and CTLA-4 Pathways.
Yunlong Zhao, Calvin K Lee, +8 authors, Enfu Hui.
Immunity, 2019 Nov 24; 51(6). PMID: 31757674    Free PMC article.
Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma.
Gulsun Erdag, Jochen T Schaefer, +5 authors, Craig L Slingluff.
Cancer Res, 2012 Jan 24; 72(5). PMID: 22266112    Free PMC article.
Highly Cited.
Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma.
Jeffrey Weber, Mario Mandala, +32 authors, CheckMate 238 Collaborators.
N Engl J Med, 2017 Sep 12; 377(19). PMID: 28891423
Highly Cited.
Gemcitabine nanoparticles promote antitumor immunity against melanoma.
Yuan Zhang, Xin Bush, Bingfang Yan, Justin A Chen.
Biomaterials, 2018 Nov 06; 189. PMID: 30388589    Free PMC article.
Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade.
Jun Zhou, Kathleen M Mahoney, +13 authors, F Stephen Hodi.
Cancer Immunol Res, 2017 May 20; 5(6). PMID: 28522460    Free PMC article.
Highly Cited.
Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response.
Gang Chen, Alexander C Huang, +36 authors, Wei Guo.
Nature, 2018 Aug 10; 560(7718). PMID: 30089911    Free PMC article.
Highly Cited.
Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression.
Viktor Fleming, Xiaoying Hu, +5 authors, Viktor Umansky.
Front Immunol, 2018 Mar 20; 9. PMID: 29552012    Free PMC article.
Highly Cited. Review.
Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs.
Brian J Christmas, Christine I Rafie, +9 authors, Evanthia T Roussos Torres.
Cancer Immunol Res, 2018 Oct 21; 6(12). PMID: 30341213    Free PMC article.
A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma.
Susan M Hiniker, Sunil A Reddy, +6 authors, Susan J Knox.
Int J Radiat Oncol Biol Phys, 2016 Sep 30; 96(3). PMID: 27681753    Free PMC article.
Highly Cited.
TIGIT: a novel immunotherapy target moving from bench to bedside.
Benjamin L Solomon, Ignacio Garrido-Laguna.
Cancer Immunol Immunother, 2018 Sep 21; 67(11). PMID: 30232519
Highly Cited. Review.
Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models.
Li Shen, Michael Ciesielski, +6 authors, Roberto Pili.
PLoS One, 2012 Feb 04; 7(1). PMID: 22303460    Free PMC article.
Exercise Behaviors and Fatigue in Patients Receiving Immunotherapy for Advanced Melanoma: A Cross-Sectional Survey via Social Media.
Amelia Hyatt, Allison Drosdowsky, +5 authors, Donna Milne.
Integr Cancer Ther, 2019 Aug 07; 18. PMID: 31382768    Free PMC article.
Prognostic Value of Baseline Neutrophil-to-Lymphocyte Ratio in Outcome of Immune Checkpoint Inhibitors.
Xianhe Xie, Junjin Liu, +7 authors, Xuewen Wang.
Cancer Invest, 2019 Jul 16; 37(6). PMID: 31304800
Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option.
Maartje W Rohaan, Joost H van den Berg, Pia Kvistborg, John B A G Haanen.
J Immunother Cancer, 2018 Oct 05; 6(1). PMID: 30285902    Free PMC article.
Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients.
M F Sanmamed, J L Perez-Gracia, +17 authors, I Melero.
Ann Oncol, 2017 Jun 09; 28(8). PMID: 28595336    Free PMC article.
Highly Cited.
PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation.
Muhammad Zaeem Noman, Giacomo Desantis, +5 authors, Salem Chouaib.
J Exp Med, 2014 Apr 30; 211(5). PMID: 24778419    Free PMC article.
Highly Cited.
Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.
O Michielin, A C J van Akkooi, +3 authors, ESMO Guidelines Committee. Electronic address:
Ann Oncol, 2019 Oct 01; 30(12). PMID: 31566661
Highly Cited.
Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer.
Cristina Iclozan, Scott Antonia, +2 authors, Dmitry Gabrilovich.
Cancer Immunol Immunother, 2013 Apr 17; 62(5). PMID: 23589106    Free PMC article.
Highly Cited.
Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients.
Jennifer S Ko, Arnold H Zea, +10 authors, James H Finke.
Clin Cancer Res, 2009 Mar 12; 15(6). PMID: 19276286
Highly Cited.
Improved overall survival in melanoma with combined dabrafenib and trametinib.
Caroline Robert, Boguslawa Karaszewska, +24 authors, Dirk Schadendorf.
N Engl J Med, 2014 Nov 18; 372(1). PMID: 25399551
Highly Cited.
PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?
Zijun Y Xu-Monette, Mingzhi Zhang, Jianyong Li, Ken H Young.
Front Immunol, 2017 Dec 20; 8. PMID: 29255458    Free PMC article.
Highly Cited. Review.
PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome.
Hashem O Alsaab, Samaresh Sau, +4 authors, Arun K Iyer.
Front Pharmacol, 2017 Sep 08; 8. PMID: 28878676    Free PMC article.
Highly Cited. Review.
Anthousa Kythreotou, Abdul Siddique, +2 authors, David J Pinato.
J Clin Pathol, 2017 Nov 04; 71(3). PMID: 29097600
Highly Cited. Review.
The number and localization of CD68+ and CD163+ macrophages in different stages of cutaneous melanoma.
Satu Salmi, Hanna Siiskonen, +5 authors, Sanna Pasonen-Seppänen.
Melanoma Res, 2018 Nov 07; 29(3). PMID: 30399061    Free PMC article.
Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma.
Fei Zhao, Kathy Evans, +6 authors, Brent A Hanks.
Cancer Immunol Res, 2018 Sep 14; 6(12). PMID: 30209062    Free PMC article.
Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.
Daniel G Coit, John A Thompson, +27 authors, Anita M Engh.
J Natl Compr Canc Netw, 2019 Apr 09; 17(4). PMID: 30959471
Highly Cited.
Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients.
Julien Fourcade, Zhaojun Sun, +6 authors, Hassane M Zarour.
J Exp Med, 2010 Sep 08; 207(10). PMID: 20819923    Free PMC article.
Highly Cited.
Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell-mediated tumor regression.
Anders Etzerodt, Kyriaki Tsalkitzi, +9 authors, Toby Lawrence.
J Exp Med, 2019 Aug 04; 216(10). PMID: 31375534    Free PMC article.
Highly Cited.
Biomarkers for Clinical Benefit of Immune Checkpoint Inhibitor Treatment-A Review From the Melanoma Perspective and Beyond.
Kristina Buder-Bakhaya, Jessica C Hassel.
Front Immunol, 2018 Jul 14; 9. PMID: 30002656    Free PMC article.
Highly Cited. Review.
Pro-tumor activities of macrophages in the progression of melanoma.
Huafeng Wang, Luhong Yang, +2 authors, Lijuan Zhang.
Hum Vaccin Immunother, 2017 Apr 26; 13(7). PMID: 28441072    Free PMC article.
Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.
James Larkin, Vanna Chiarion-Sileni, +28 authors, Jedd D Wolchok.
N Engl J Med, 2019 Sep 29; 381(16). PMID: 31562797
Highly Cited.
Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution.
Line Pedersen, Manja Idorn, +12 authors, Pernille Hojman.
Cell Metab, 2016 Feb 21; 23(3). PMID: 26895752
Highly Cited.
Pre-clinical development of Listeria-based nanovaccines as immunotherapies for solid tumours: insights from melanoma.
Hector Terán-Navarro, Ricardo Calderon-Gonzalez, +13 authors, Carmen Álvarez-Domínguez.
Oncoimmunology, 2019 Feb 05; 8(2). PMID: 30713801    Free PMC article.
Regulatory T-cell heterogeneity and the cancer immune response.
Kirsten A Ward-Hartstonge, Roslyn A Kemp.
Clin Transl Immunology, 2017 Oct 07; 6(9). PMID: 28983402    Free PMC article.
PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC.
Marzia Del Re, Riccardo Marconcini, +12 authors, Romano Danesi.
Br J Cancer, 2018 Mar 07; 118(6). PMID: 29509748    Free PMC article.
Highly Cited.
Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy.
Lillian Sun, Paul E Clavijo, +12 authors, Clint T Allen.
JCI Insight, 2019 Apr 05; 4(7). PMID: 30944253    Free PMC article.
Highly Cited.
Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy.
Melvyn T Chow, Aleksandra J Ozga, +6 authors, Andrew D Luster.
Immunity, 2019 May 18; 50(6). PMID: 31097342    Free PMC article.
Highly Cited.
Entinostat Helps Thwart Immunotherapy Resistance.
Cancer Discov, 2019 Apr 03; 9(6). PMID: 30936082
The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.
Vyara Matson, Jessica Fessler, +5 authors, Thomas F Gajewski.
Science, 2018 Jan 06; 359(6371). PMID: 29302014    Free PMC article.
Highly Cited.
PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance.
Vivek Verma, Rajeev K Shrimali, +25 authors, Samir N Khleif.
Nat Immunol, 2019 Jul 31; 20(9). PMID: 31358999    Free PMC article.
Highly Cited.
Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia.
Nicole E Scharping, Ashley V Menk, +2 authors, Greg M Delgoffe.
Cancer Immunol Res, 2016 Dec 13; 5(1). PMID: 27941003    Free PMC article.
Highly Cited.
Stromal Cells in the Tumor Microenvironment.
Alice E Denton, Edward W Roberts, Douglas T Fearon.
Adv Exp Med Biol, 2018 Aug 30; 1060. PMID: 30155624
Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells.
Theodore Kouo, Lanqing Huang, +4 authors, Elizabeth Jaffee.
Cancer Immunol Res, 2015 Feb 19; 3(4). PMID: 25691328    Free PMC article.
Highly Cited.
Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors.
Jeffrey M Conroy, Sarabjot Pabla, +37 authors, Carl Morrison.
J Immunother Cancer, 2019 Jan 27; 7(1). PMID: 30678715    Free PMC article.
Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.
Jedd D Wolchok, Axel Hoos, +9 authors, F Stephen Hodi.
Clin Cancer Res, 2009 Nov 26; 15(23). PMID: 19934295
Highly Cited.
Elevated chronic inflammatory factors and myeloid-derived suppressor cells indicate poor prognosis in advanced melanoma patients.
Huanhuan Jiang, Christoffer Gebhardt, +4 authors, Viktor Umansky.
Int J Cancer, 2014 Oct 30; 136(10). PMID: 25353097
All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients.
Noweeda Mirza, Mayer Fishman, +6 authors, Dmitry I Gabrilovich.
Cancer Res, 2006 Sep 20; 66(18). PMID: 16982775    Free PMC article.
Highly Cited.
Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.
V Gopalakrishnan, C N Spencer, +67 authors, J A Wargo.
Science, 2017 Nov 04; 359(6371). PMID: 29097493    Free PMC article.
Highly Cited.
TIGIT predominantly regulates the immune response via regulatory T cells.
Sema Kurtulus, Kaori Sakuishi, +6 authors, Ana C Anderson.
J Clin Invest, 2015 Sep 29; 125(11). PMID: 26413872    Free PMC article.
Highly Cited.
Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab.
Christoffer Gebhardt, Alexandra Sevko, +10 authors, Viktor Umansky.
Clin Cancer Res, 2015 Aug 21; 21(24). PMID: 26289067
Highly Cited.
Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha.
Matthew Kraman, Paul J Bambrough, +6 authors, Douglas T Fearon.
Science, 2010 Nov 06; 330(6005). PMID: 21051638
Highly Cited.
High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma.
J Zaragoza, A Caille, +4 authors, L Machet.
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.
Highly Cited.
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
Highly Cited.
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.
Highly Cited.
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.
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.
Kim H T Paraiso, Keiran S M Smalley.
Biochem Pharmacol, 2013 Feb 05; 85(8). PMID: 23376122
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
Highly Cited.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.