Tumor Microenvironment in melanoma: Comparison
Please note this is a comparison between Version 3 by Bruce Ren and Version 2 by Bruce Ren.

Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was one of the first tumor types to benefit from this new care frontier by introducing specific inhibitors for v-Raf murine sarcoma viral oncogene homolog B (BRAF), mitogen-activated protein kinase (MEK), v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and, recently, immunotherapy. However, despite the progress made in the melanoma treatment, primary and/or acquired drug resistance remains an unresolved problem. The molecular dynamics that promote this phenomenon are very complex but several studies have shown that the tumor microenvironment (TME) plays, certainly, a key role. In this review, we will describe the new melanoma treatment approaches and we will analyze the mechanisms by which TME promotes resistance to targeted therapy and immunotherapy.

  • Melanoma
  • targeted therapy
  • immunotherapy
  • tumor microenvironment
  • therapeutic resistance
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References

  1. Ferlay, J.; Shin, H.-R.; Bray, F.; Forman, D.; Mathers, C.; Parkin, D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 2010, 127, 2893–2917, doi:10.1002/ijc.25516.
  2. Siegel, R.L.; Mph, K.D.M.; Jemal, A. Cancer statistics, 2020. CA: A Cancer J. Clin. 2020, 70, 7–30, doi:10.3322/caac.21590.
  3. Bennett, D.C. REVIEW ARTICLE: How to make a melanoma: what do we know of the primary clonal events? Pigment. Cell Melanoma Res. 2007, 21, 27–38, doi:10.1111/j.1755-148x.2007.00433.x.
  4. Shain, A.H.; Yeh, I.; Kovalyshyn, I.; Sriharan, A.; Talevich, E.; Gagnon, A.; Dummer, R.; North, J.; Pincus, L.; Ruben, B.; et al. The Genetic Evolution of Melanoma from Precursor Lesions. New Engl. J. Med. 2015, 373, 1926–1936, doi:10.1056/nejmoa1502583.
  5. Sanlorenzo, M.; Vujic, I.; Posch, C.; Dajee, A.; Yen, A.; Kim, S.; Ashworth, M.; Rosenblum, M.D.; Algazi, A.; Osella-Abate, S.; et al. Melanoma immunotherapy. Cancer Biol. Ther. 2014, 15, 665–74, doi:10.4161/cbt.28555.
  6. Wolchok, J.D.; Chiarion-Sileni, V.; Gonzalez, R.; Rutkowski, P.; Grob, J.-J.; Cowey, C.L.; Lao, C.D.; Wagstaff, J.; Schadendorf, D.; Ferrucci, P.F.; et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. New Engl. J. Med. 2017, 377, 1345–1356, doi:10.1056/nejmoa1709684.
  7. Dummer, R.; Ascierto, P.A.; Gogas, H.; Arance, A.; Mandalà, M.; Liszkay, G.; Garbe, C.; Schadendorf, D.; Krajsová, I.; Gutzmer, R.; et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF -mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018, 19, 603–615, doi:10.1016/s1470-2045(18)30142-6.
  8. Long, G.V.; Flaherty, K.T.; Stroyakovskiy, D.; Gogas, H.; Levchenko, E.; De Braud, F.; Larkin, J.; Garbe, C.; Jouary, T.; Hauschild, A.; et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann. Oncol. 2017, 28, 1631–1639, doi:10.1093/annonc/mdx176.
  9. Ascierto, P.A.; Ferrucci, P.F.; Fisher, R.; Del Vecchio, M.; Atkinson, V.; Schmidt, H.; Schachter, J.; Queirolo, P.; Long, G.V.; Di Giacomo, A.M.; et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat. Med. 2019, 25, 941–946, doi:10.1038/s41591-019-0448-9.
  10. Wu, T.; Dai, Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017, 387, 61–68, doi:10.1016/j.canlet.2016.01.043.
  11. Conciatori, F.; Bazzichetto, C.; Falcone, I.; Pilotto, S.; Bria, E.; Cognetti, F.; Milella, M.; Ciuffreda, L. Role of mTOR Signaling in Tumor Microenvironment: An Overview. Int. J. Mol. Sci. 2018, 19, 2453, doi:10.3390/ijms19082453.
  12. Kubo, N.; Araki, K.; Kuwano, H.; Shirabe, K. Cancer-associated fibroblasts in hepatocellular carcinoma. World J. Gastroenterol. 2016, 22, 6841–6850,, doi:10.3748/wjg.v22.i30.6841.
  13. Yuan, Y.; Jiang, Y.-C.; Sun, C.; Chen, Q. Role of the tumor microenvironment in tumor progression and the clinical applications (Review). Oncol. Rep. 2016, 35, 2499–2515, doi:10.3892/or.2016.4660.
  14. Hu, B.; Wu, Z.; Jin, H.; Hashimoto, N.; Liu, T.; Phan, S.H. CCAAT/Enhancer-Binding Protein β Isoforms and the Regulation of α-Smooth Muscle Actin Gene Expression by IL-1β. J. Immunol. 2004, 173, 4661–4668, doi:10.4049/jimmunol.173.7.4661.
  15. Shiga, K.; Hara, M.; Nagasaki, T.; Sato, T.; Takahashi, H.; Takeyama, H. Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth. Cancers 2015, 7, 2443–2458, doi:10.3390/cancers7040902.
  16. Hutchenreuther, J.; Vincent, K.; Norley, C.; Racanelli, M.; Gruber, S.B.; Johnson, T.M.; Fullen, D.R.; Raskin, L.; Perbal, B.; Holdsworth, D.W.; et al. Activation of cancer-associated fibroblasts is required for tumor neovascularization in a murine model of melanoma. Matrix Biol. 2018, 74, 52–61, doi:10.1016/j.matbio.2018.06.003.
  17. Cornil, I.; Theodorescu, D.; Man, S.; Herlyn, M.; Jambrosic, J.; Kerbel, R.S. Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression. Proc. Natl. Acad. Sci. 1991, 88, 6028–6032, doi:10.1073/pnas.88.14.6028.
  18. Jobe, N.P.; Rösel, D.; Dvořánková, B.; Kodet, O.; Lacina, L.; Mateu, R.; Smetana, K.; Brábek, J.; Smetana, K. Simultaneous blocking of IL-6 and IL-8 is sufficient to fully inhibit CAF-induced human melanoma cell invasiveness. Histochem. Cell Biol. 2016, 146, 205–217, doi:10.1007/s00418-016-1433-8.
  19. Zhou, L.; Yang, K.; Wickett, R.R.; Kadekaro, A.L.; Zhang, Y. Targeted deactivation of cancer-associated fibroblasts by β-catenin ablation suppresses melanoma growth. Tumor Biol. 2016, 37, 14235–14248, doi:10.1007/s13277-016-5293-6.
  20. Guo, Y.; Zhang, X.; Zeng, W.; Zhang, J.; Cai, L.; Wu, Z.; Su, J.; Xiao, Y.; Liu, N.; Tang, L.; et al. TRAF6 Activates Fibroblasts to Cancer-Associated Fibroblasts through FGF19 in Tumor Microenvironment to Benefit the Malignant Phenotype of Melanoma Cells. J. Investig. Dermatol. 2020, doi:10.1016/j.jid.2020.03.950.
  21. Straussman, R.; Morikawa, T.; Shee, K.; Barzily-Rokni, M.; Qian, Z.R.; Du, J.; Davis, A.; Mongare, M.M.; Gould, J.; Frederick, D.T.; et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nat. Cell Biol. 2012, 487, 500–504, doi:10.1038/nature11183.
  22. Capparelli, C.; Rosenbaum, S.; Berger, A.C.; Aplin, A.E. Fibroblast-derived Neuregulin 1 Promotes Compensatory ErbB3 Receptor Signaling in Mutant BRAF Melanoma*. J. Biol. Chem. 2015, 290, 24267–24277, doi:10.1074/jbc.M115.657270.
  23. Fedorenko, I.V.; Wargo, J.A.; Flaherty, K.T.; Messina, J.L.; Smalley, K.S. BRAF Inhibition Generates a Host-Tumor Niche that Mediates Therapeutic Escape. J. Investig. Dermatol. 2015, 135, 3115–3124, doi:10.1038/jid.2015.329.
  24. Hirata, E.; Girotti, M.R.; Viros, A.; Hooper, S.; Spencer-Dene, B.; Matsuda, M.; Larkin, J.; Marais, R.; Sahai, E. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 2015, 27, 574–88, doi:10.1016/j.ccell.2015.03.008.
  25. Grivennikov, S.I.; Greten, F.R.; Karin, M. Immunity, Inflammation, and Cancer. Cell 2010, 140, 883–899, doi:10.1016/j.cell.2010.01.025.
  26. Kaur, A.; Webster, M.R.; Marchbank, K.; Behera, R.; Ndoye, A.; Kugel, C.H.; Dang, V.M.; Appleton, J.; O’Connell, M.P.; Cheng, P.; et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nat. Cell Biol. 2016, 532, 250–254, doi:10.1038/nature17392.
  27. Takahashi, H.; Sakakura, K.; Kawabata-Iwakawa, R.; Rokudai, S.; Toyoda, M.; Nishiyama, M.; Chikamatsu, K. Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma. Cancer Immunol. Immunother. 2015, 64, 1407–1417, doi:10.1007/s00262-015-1742-0.
  28. Zhang, A.; Qian, Y.; Ye, Z.; Chen, H.; Xie, H.; Zhou, L.; Shen, Y.; Zheng, S. Cancer-associated fibroblasts promote M2 polarization of macrophages in pancreatic ductal adenocarcinoma. Cancer Med. 2017, 6, 463–470, doi:10.1002/cam4.993.
  29. Costa, A.; Kieffer, Y.; Scholer-Dahirel, A.; Pelon, F.; Bourachot, B.; Cardon, M.; Sirven, P.; Magagna, I.; Fuhrmann, L.; Bernard, C.; et al. Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. Cancer Cell 2018, 33, 463–479.e10, doi:10.1016/j.ccell.2018.01.011.
  30. Ziani, L.; Ben Safta-Saadoun, T.; Gourbeix, J.; Cavalcanti, A.; Robert, C.; Favre, G.; Chouaib, S.; Thiery, J. Melanoma-associated fibroblasts decrease tumor cell susceptibility to NK cell-mediated killing through matrix-metalloproteinases secretion. Oncotarget 2017, 8, 19780–19794, doi:10.18632/oncotarget.15540.
  31. Li, Z.; Zhou, J.; Zhang, J.; Li, S.; Wang, H.; Du, J. Cancer-associated fibroblasts promote PD-L1 expression in mice cancer cells via secreting CXCL5. Int. J. Cancer 2019, 145, 1946–1957, doi:10.1002/ijc.32278.
  32. Lee, J.H.; Shklovskaya, E.; Lim, S.Y.; Carlino, M.S.; Menzies, A.M.; Stewart, A.; Pedersen, B.; Irvine, M.; Alavi, S.; Yang, J.; et al. Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition. Nat. Commun. 2020, 11, 1–12, doi:10.1038/s41467-020-15726-7.
  33. Li, G.; Satyamoorthy, K.; Herlyn, M. N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res. 2001, 61, 3819–3825.
  34. Flach, E.H.; Rebecca, V.W.; Herlyn, M.; Smalley, K.S.; Anderson, A.R. Fibroblasts Contribute to Melanoma Tumor Growth and Drug Resistance. Mol. Pharm. 2011, 8, 2039–2049, doi:10.1021/mp200421k.
  35. Tiago, M.; De Oliveira, E.M.; Brohem, C.A.; Pennacchi, P.C.; Paes, R.D.; Haga, R.B.; Campa, A.; Barros, S.B.D.M.; Smalley, K.S.; Maria-Engler, S.S. Fibroblasts Protect Melanoma Cells from the Cytotoxic Effects of Doxorubicin. Tissue Eng. Part A 2014, 20, 2412–2421, doi:10.1089/ten.tea.2013.0473.
  36. Singer, A.; Bosselut, R. CD4⧸CD8 Coreceptors in Thymocyte Development, Selection, and Lineage Commitment: Analysis of the CD4⧸CD8 Lineage Decision. Advances in Immunology 2004, 83, 91–131, doi:10.1016/s0065-2776(04)83003-7.
  37. Luckheeram, R.V.; Zhou, R.; Verma, A.D.; Xia, B. CD4+T Cells: Differentiation and Functions. Clin. Dev. Immunol. 2012, 2012, 1–12, doi:10.1155/2012/925135.
  38. Bazzichetto, C.; Conciatori, F.; Pallocca, M.; Falcone, I.; Fanciulli, M.; Cognetti, F.; Milella, M.; Ciuffreda, L. PTEN as a Prognostic/Predictive Biomarker in Cancer: An Unfulfilled Promise? Cancers 2019, 11, 435, doi:10.3390/cancers11040435.
  39. Cetintas, V.B.; Batada, N.N. Is there a causal link between PTEN deficient tumors and immunosuppressive tumor microenvironment? J. Transl. Med. 2020, 18, 45–11, doi:10.1186/s12967-020-02219-w.
  40. Dong, Y.; Richards, J.-A.; Gupta, R.; Aung, P.P.; Emley, A.; Kluger, Y.; Dogra, S.K.; Mahalingam, M.; Wajapeyee, N. PTEN functions as a melanoma tumor suppressor by promoting host immune response. Oncogene 2013, 33, 4632–4642, doi:10.1038/onc.2013.409.
  41. Peng, W.; Chen, J.Q.; Liu, C.; Malu, S.; Creasy, C.; Tetzlaff, M.T.; Xu, C.; McKenzie, J.A.; Zhang, C.; Liang, X.; et al. Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer Discov. 2015, 6, 202–216, doi:10.1158/2159-8290.cd-15-0283.
  42. Xia, A.; Zhang, Y.; Xu, J.; Yin, T.; Lu, X.-J. T Cell Dysfunction in Cancer Immunity and Immunotherapy. Front. Immunol. 2019, 10, 1719, doi:10.3389/fimmu.2019.01719.
  43. Fourcade, J.; Sun, Z.; Benallaoua, M.; Guillaume, P.; Luescher, I.F.; Sander, C.; Kirkwood, J.M.; Kuchroo, V.; Zarour, H.M. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 2010, 207, 2175–2186, doi:10.1084/jem.20100637.
  44. Chauvin, J.-M.; Pagliano, O.; Fourcade, J.; Sun, Z.; Wang, H.; Sander, C.; Kirkwood, J.M.; Chen, T.-H.T.; Maurer, M.; Korman, A.J.; et al. TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients. J. Clin. Investig. 2015, 125, 2046–58, doi:10.1172/JCI80445.
  45. Li, H.; Van Der Leun, A.M.; Yofe, I.; Lubling, Y.; Gelbard-Solodkin, D.; Van Akkooi, A.C.; Braber, M.V.D.; Rozeman, E.A.; Haanen, J.B.; Blank, C.U.; et al. Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma. Cell 2019, 176, 775–789.e18, doi:10.1016/j.cell.2018.11.043.
  46. Marshall, J.S.; Warrington, R.; Watson, W.; Kim, H.L. An introduction to immunology and immunopathology. Allergy, Asthma Clin. Immunol. 2018, 14, 49, doi:10.1186/s13223-018-0278-1.
  47. Somasundaram, R.; Zhang, G.; Fukunaga-Kalabis, M.; Perego, M.; Krepler, C.; Xu, X.; Wagner, C.; Hristova, D.; Zhang, J.; Tian, T.; et al. Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nat. Commun. 2017, 8, 607, doi:10.1038/s41467-017-00452-4.
  48. Griss, J.; Bauer, W.; Wagner, C.; Simon, M.; Chen, M.; Grabmeier-Pfistershammer, K.; Maurer-Granofszky, M.; Roka, F.; Penz, T.; Bock, C.; et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 2019, 10, 1–14, doi:10.1038/s41467-019-12160-2.
  49. Cabrita, R.; Lauss, M.; Sanna, A.; Donia, M.; Larsen, M.S.; Mitra, S.; Johansson, I.; Phung, B.; Harbst, K.; Vallon-Christersson, J.; et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 2020, 577, 561–565, doi:10.1038/s41586-019-1914-8.
  50. Amaria, R.N.; Reddy, S.M.; Tawbi, H.A.; Davies, M.A.; Ross, M.I.; Glitza, I.C.; Cormier, J.N.; Lewis, C.; Hwu, W.-J.; Hanna, E.; et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 2018, 24, 1649–1654, doi:10.1038/s41591-018-0197-1.
  51. Helmink, B.A.; Reddy, S.M.; Gao, J.; Zhang, S.; Basar, R.; Thakur, R.; Yizhak, K.; Sade-Feldman, M.; Blando, J.; Han, G.; et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nat. Cell Biol. 2020, 577, 549–555, doi:10.1038/s41586-019-1922-8.
  52. Pahl, J.H.; Cerwenka, A. Tricking the balance: NK cells in anti-cancer immunity. Immunobiol. 2017, 222, 11–20, doi:10.1016/j.imbio.2015.07.012.
  53. Freud, A.G.; Mundy-Bosse, B.L.; Yu, J.; Caligiuri, M.A. The Broad Spectrum of Human Natural Killer Cell Diversity. Immun. 2017, 47, 820–833, doi:10.1016/j.immuni.2017.10.008.
  54. Cristiani, C.M.; Garofalo, C.; Passacatini, L.C.; Carbone, E. New avenues for melanoma immunotherapy: Natural Killer cells? Scand. J. Immunol. 2020, 91, e12861, doi:10.1111/sji.12861.
  55. López-Cobo, S.; Pieper, N.; Campos-Silva, C.; García-Cuesta, E.M.; Reyburn, H.T.; Paschen, A.; Valés-Gómez, M. Impaired NK cell recognition of vemurafenib-treated melanoma cells is overcome by simultaneous application of histone deacetylase inhibitors. OncoImmunology 2017, 7, e1392426, doi:10.1080/2162402X.2017.1392426.
  56. Kondělková, K.; Vokurková, D.; Krejsek, J.; Borska, L.; Fiala, Z.; Andrys, C. Regulatory T cells (Treg) and Their Roles in Immune System with Respect to Immunopathological Disorders. Acta Medica (Hradec Kralove, Czech Republic) 2010, 53, 73–77, doi:10.14712/18059694.2016.63.
  57. Chaudhary, B.; Elkord, E. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting. Vaccines 2016, 4, 28, doi:10.3390/vaccines4030028.
  58. Ascierto, P.A.; Napolitano, M.; Celentano, E.; Simeone, E.; Gentilcore, G.; Daponte, A.; Capone, M.; Caracò, C.; Calemma, R.; Beneduce, G.; et al. Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-α 2b treatment. J. Transl. Med. 2010, 8, 76, doi:10.1186/1479-5876-8-76.
  59. Shang, B.; Liu, Y.; Jiang, S.-J.; Liu, Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci. Rep. 2015, 5, srep15179, doi:10.1038/srep15179.
  60. Leslie, C.; Bowyer, S.E.; White, A.; Grieu-Iacopetta, F.; Trevenen, M.; Iacopetta, B.; Amanuel, B.; Millward, M. FOXP3+ T regulatory lymphocytes in primary melanoma are associated with BRAF mutation but not with response to BRAF inhibitor. Pathol. 2015, 47, 557–563, doi:10.1097/pat.0000000000000314.
  61. Baumgartner, J.; Wilson, C.; Palmer, B.; Richter, D.; Banerjee, A.; McCarter, M. Melanoma Induces Immunosuppression by Up-Regulating FOXP3+ Regulatory T Cells. J. Surg. Res. 2007, 141, 72–77, doi:10.1016/j.jss.2007.03.053.
  62. Sumimoto, H.; Imabayashi, F.; Iwata, T.; Kawakami, Y. The BRAF–MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J. Exp. Med. 2006, 203, 1651–1656, doi:10.1084/jem.20051848.
  63. Zappasodi, R.; Budhu, S.; Hellmann, M.D.; Postow, M.A.; Senbabaoglu, Y.; Manne, S.; Gasmi, B.; Liu, C.; Zhong, H.; Li, Y.; et al. Non-conventional Inhibitory CD4+Foxp3−PD-1hi T Cells as a Biomarker of Immune Checkpoint Blockade Activity. Cancer Cell 2018, 33, 1017–1032.e7, doi:10.1016/j.ccell.2018.05.009.
  64. Zhang, B.; Chikuma, S.; Hori, S.; Fagarasan, S.; Honjo, T. Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. Proc. Natl. Acad. Sci. 2016, 113, 8490–8495, doi:10.1073/pnas.1608873113.
  65. Gianchecchi, E.; Fierabracci, A. Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression. Front. Immunol. 2018, 9, 2374,, doi:10.3389/fimmu.2018.02374.
  66. Kamada, T.; Togashi, Y.; Tay, C.; Ha, D.; Sasaki, A.; Nakamura, Y.; Sato, E.; Fukuoka, S.; Tada, Y.; Tanaka, A.; et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc. Natl. Acad. Sci. 2019, 116, 9999–10008, doi:10.1073/pnas.1822001116.
  67. Simeone, E.; Gentilcore, G.; Giannarelli, D.; Grimaldi, A.M.; Caracò, C.; Curvietto, M.; Esposito, A.; Paone, M.; Palla, M.; Cavalcanti, E.; et al. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol. Immunother. 2014, 63, 675–683, doi:10.1007/s00262-014-1545-8.
  68. Simpson, T.R.; Li, F.; Montalvo-Ortiz, W.; Sepulveda, M.A.; Bergerhoff, K.; Arce, F.; Roddie, C.; Henry, J.Y.; Yagita, H.; Wolchok, J.D.; et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma. J. Exp. Med. 2013, 210, 1695–1710, doi:10.1084/jem.20130579.
  69. Solito, S.; Marigo, I.; Pinton, L.; Damuzzo, V.; Mandruzzato, S.; Bronte, V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann. New York Acad. Sci. 2014, 1319, 47–65, doi:10.1111/nyas.12469.
  70. Gabrilovich, D.I. Myeloid-Derived Suppressor Cells. Cancer Immunol. Res. 2017, 5, 3–8, doi:10.1158/2326-6066.cir-16-0297.
  71. Umansky, V.; Sevko, A.; Gebhardt, C.; Utikal, J. Myeloid-derived suppressor cells in malignant melanoma. J. der Dtsch. Dermatol. Ges. 2014, 12, 1021–1027, doi:10.1111/ddg.12411.
  72. Huber, V.; Vallacchi, V.; Fleming, V.; Hu, X.; Cova, A.; Dugo, M.; Shahaj, E.; Sulsenti, R.; Vergani, E.; Filipazzi, P.; et al. Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma. J. Clin. Investig. 2018, 128, 5505–5516, doi:10.1172/jci98060.
  73. Gebhardt, C.; Sevko, A.; Jiang, H.; Lichtenberger, R.; Reith, M.; Tarnanidis, K.; Holland-Letz, T.; Umansky, L.; Beckhove, P.; Sucker, A.; et al. Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab. Clin. Cancer Res. 2015, 21, 5453–5459, doi:10.1158/1078-0432.ccr-15-0676.
  74. Steinberg, S.M.; Shabaneh, T.B.; Zhang, P.; Martyanov, V.; Li, Z.; Malik, B.T.; Wood, T.A.; Boni, A.; Molodtsov, A.; Angeles, C.V.; et al. Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors. Cancer Res. 2017, 77, 1599–1610, doi:10.1158/0008-5472.CAN-16-1755.
  75. Yuan, A.; Chen, J.J.; Yang, P. Pathophysiology of Tumor-Associated Macrophages. Advances in Virus Research 2008, 45, 199–223, doi:10.1016/s0065-2423(07)00008-x.
  76. Yahaya, M.A.F.; Lila, M.A.M.; Ismail, S.; Zainol, M.; Afizan, N.A.R.N.M. Tumour-Associated Macrophages (TAMs) in Colon Cancer and How to Reeducate Them. J. Immunol. Res. 2019, 2019, 1–9, doi:10.1155/2019/2368249.
  77. Donzelli, S.; Milano, E.; Pruszko, M.; Sacconi, A.; Masciarelli, S.; Iosue, I.; Melucci, E.; Gallo, E.; Terrenato, I.; Mottolese, M.; et al. Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages. Breast Cancer Res. 2018, 20, 59, doi:10.1186/s13058-018-0990-2.
  78. Liu, H.; Yang, L.; Qi, M.; Zhang, J. NFAT1 enhances the effects of tumor-associated macrophages on promoting malignant melanoma growth and metastasis. Biosci. Rep. 2018, 38, 38,, doi:10.1042/bsr20181604.
  79. Wanderley, C.W.; Colón, D.; Luiz, J.P.M.; Oliveira, F.F.; Viacava, P.R.; A Leite, C.; A Pereira, J.; Silva, C.M.; Silva, C.R.; Silva, R.L.; et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1- profile in a TLR4-dependent manner. Cancer Res. 2018, 78, 5891–5900,, doi:10.1158/0008-5472.can-17-3480.
  80. Gerloff, D.; Lützkendorf, J.; Moritz, R.K.; Wersig, T.; Mäder, K.; Müller, L.P.; Sunderkötter, C. Melanoma-Derived Exosomal miR-125b-5p Educates Tumor Associated Macrophages (TAMs) by Targeting Lysosomal Acid Lipase A (LIPA). Cancers 2020, 12, 464, doi:10.3390/cancers12020464.
  81. Smith, M.P.; Sanchez-Laorden, B.; O’Brien, K.; Brunton, H.; Ferguson, J.; Young, H.L.; Dhomen, N.; Flaherty, K.T.; Frederick, D.T.; Cooper, Z.A.; et al. The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFα. Cancer Discov. 2014, 4, 1214–1229, doi:10.1158/2159-8290.CD-13-1007.
  82. Wang, T.; Xiao, M.; Ge, Y.; Krepler, C.; Belser, E.; Coral, A.L.; Xu, X.; Zhang, G.; Azuma, R.; Liu, Q.; et al. BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth. Clin. Cancer Res. 2015, 21, 1652–1664, doi:10.1158/1078-0432.ccr-14-1554.
  83. Gordon, S.R.; Maute, R.L.; Dulken, B.W.; Hutter, G.; George, B.M.; McCracken, M.N.; Gupta, R.; Tsai, J.M.; Sinha, R.; Corey, D.; et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nat. Cell Biol. 2017, 545, 495–499, doi:10.1038/nature22396.
  84. Kuklinski, L.F.; Yan, S.; Li, Z.; Fisher, J.L.; Cheng, C.; Noelle, R.J.; Angeles, C.V.; Turk, M.J.; Ernstoff, M.S. VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Cancer Immunol. Immunother. 2018, 67, 1113–1121, doi:10.1007/s00262-018-2169-1.
  85. Lines, J.L.; Sempere, L.F.; Wang, L.; Pantazi, E.; Mak, J.; O’Connell, S.; Ceeraz, S.; Suriawinata, A.A.; Yan, S.; Ernstoff, M.S.; et al. VISTA is an immune checkpoint molecule for human T cells. Cancer Res. 2014, 74, 1924–1932, doi:10.1158/0008-5472.CAN-13-1504.
  86. Kakavand, H.; A Jackett, L.; Menzies, A.M.; Gide, T.N.; Carlino, M.S.; Saw, R.P.M.; Thompson, J.F.; Wilmott, J.S.; Long, G.V.; Scolyer, R.A. Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod. Pathol. 2017, 30, 1666–1676, doi:10.1038/modpathol.2017.89.
  87. Rosenbaum, S.R.; Knecht, M.; Mollaee, M.; Zhong, Z.; Erkes, D.A.; McCue, P.A.; Chervoneva, I.; Berger, A.C.; Lo, J.A.; Fisher, D.E.; et al. FOXD3 Regulates VISTA Expression in Melanoma. Cell Rep. 2020, 30, 510–524.e6, doi:10.1016/j.celrep.2019.12.036.
  88. Zhang, Y.; Wu, L.; Li, Z.; Zhang, W.; Luo, F.; Chu, Y.; Chen, G. Glycocalyx-Mimicking Nanoparticles Improve Anti-PD-L1 Cancer Immunotherapy through Reversion of Tumor-Associated Macrophages. Biomacromolecules 2018, 19, 2098–2108, doi:10.1021/acs.biomac.8b00305.
  89. Peranzoni, E.; Lemoine, J.; Vimeux, L.; Feuillet, V.; Barrin, S.; Kantari-Mimoun, C.; Bercovici, N.; Guérin, M.; Biton, J.; Ouakrim, H.; et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment. Proc. Natl. Acad. Sci. 2018, 115, E4041–E4050, doi:10.1073/pnas.1720948115.
  90. Klarquist, J.S.; Janssen, E.M. Melanoma-infiltrating dendritic cells. OncoImmunology 2012, 1, 1584–1593, doi:10.4161/onci.22660.
  91. Álvarez-Domínguez, C.; Calderón-González, R.; Terán-Navarro, H.; Salcines-Cuevas, D.; García-Castaño, A.; Freire, J.; Gómez-Román, J.; Rivera, F. Dendritic cell therapy in melanoma. Ann. Transl. Med. 2017, 5, 386, doi:10.21037/atm.2017.06.13.
  92. Wu, L.; Dakic, A. Development of dendritic cell system. Cell. Mol. Immunol. 2004, 1, 112–8.
  93. Passarelli, A.; Mannavola, F.; Stucci, L.S.; Tucci, M.; Silvestris, F. Immune system and melanoma biology: a balance between immunosurveillance and immune escape. Oncotarget 2017, 8, 106132–106142, doi:10.18632/oncotarget.22190.
  94. González, M.L.; Oosterhoff, D.; Lindenberg, J.J.; Milenova, I.; Lougheed, S.M.; Martiáñez, T.; Dekker, H.; Quixabeira, D.C.A.; Hangalapura, B.; Joore, J.; et al. Constitutively active GSK3β as a means to bolster dendritic cell functionality in the face of tumour-mediated immune suppression. OncoImmunology 2019, 8, e1631119–18, doi:10.1080/2162402X.2019.1631119.
  95. Van De Ven, R.; Lindenberg, J.J.; Oosterhoff, D.; De Gruijl, T.D. Dendritic Cell Plasticity in Tumor-Conditioned Skin: CD14+ Cells at the Cross-Roads of Immune Activation and Suppression. Front. Immunol. 2013, 4, 403,, doi:10.3389/fimmu.2013.00403.
  96. González, M.L.; Van De Ven, R.; De Haan, H.; Sluijs, J.V.E.V.D.; Dong, W.; Van Beusechem, V.W.; De Gruijl, T.D. Oncolytic adenovirus ORCA-010 increases the type 1 T cell stimulatory capacity of melanoma-conditioned dendritic cells. Clin. Exp. Immunol. 2020, 201, 145–160,, doi:10.1111/cei.13442.
  97. Zhou, Y.; Slone, N.; Chrisikos, T.T.; Kyrysyuk, O.; Babcock, R.L.; Medik, Y.B.; Li, H.S.; Kleinerman, E.S.; Watowich, S.S. Vaccine efficacy against primary and metastatic cancer with in vitro-generated CD103+conventional dendritic cells. J. Immunother. Cancer 2020, 8, e000474, doi:10.1136/jitc-2019-000474.
  98. Chu, C.-L.; Lee, Y.-P.; Pang, C.-Y.; Lin, H.-R.; Chen, C.-S.; Wen-Sheng, W. Tyrosine kinase inhibitors modulate dendritic cell activity via confining c-Kit signaling and tryptophan metabolism. Int. Immunopharmacol. 2020, 82, 106357, doi:10.1016/j.intimp.2020.106357.
  99. Riegel, K.; Schlöder, J.; Sobczak, M.; Jonuleit, H.; Thiede, B.; Schild, H.; Rajalingam, K. RAF kinases are stabilized and required for dendritic cell differentiation and function. Cell Death Differ. 2019, 27, 1300–1315, doi:10.1038/s41418-019-0416-4.
  100. Botti, G.; Cerrone, M.; Scognamiglio, G.; Anniciello, A.; Ascierto, P.A.; Cantile, M. Microenvironment and tumor progression of melanoma: New therapeutic prospectives. J. Immunotoxicol. 2012, 10, 235–252, doi:10.3109/1547691x.2012.723767.
  101. You, D.; Jung, S.P.; Jeong, Y.; Bae, S.Y.; Lee, J.E.; Kim, S. Fibronectin expression is upregulated by PI-3K/Akt activation in tamoxifen-resistant breast cancer cells. BMB Rep. 2017, 50, 615–620, doi:10.5483/bmbrep.2017.50.12.096.
  102. Erdogan, B.; Ao, M.; White, L.M.; Means, A.L.; Brewer, B.M.; Yang, L.; Washington, M.K.; Shi, C.; Franco, O.E.; Weaver, A.M.; et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J. Cell Biol. 2017, 216, 3799–3816, doi:10.1083/jcb.201704053.
  103. Fedorenko, I.V.; Abel, E.V.; Koomen, J.M.; Fang, B.; Wood, E.R.; Chen, Y.A.; Fisher, K.J.; Iyengar, S.; Dahlman, K.B.; Wargo, J.A.; et al. Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells. Oncogene 2015, 35, 1225–35, doi:10.1038/onc.2015.188.
  104. Takada, Y.; Ye, X.; Simon, S. The integrins. Genome Biol. 2007, 8, 1–9, doi:10.1186/gb-2007-8-5-215.
  105. Huang, R.; Rofstad, E.K. Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma. J. Exp. Clin. Cancer Res. 2018, 37, 92, doi:10.1186/s13046-018-0763-x.
  106. Jang, I.; Beningo, K.A. Integrins, CAFs and Mechanical Forces in the Progression of Cancer. Cancers 2019, 11, 721, doi:10.3390/cancers11050721.
  107. Felding-Habermann, B.; Ruggeri, Z.M.; A Cheresh, D. Distinct biological consequences of integrin alpha v beta 3-mediated melanoma cell adhesion to fibrinogen and its plasmic fragments. J. Biol. Chem. 1992, 267, 5070–5077.
  108. Vannini, A.; Leoni, V.; Barboni, C.; Sanapo, M.; Zaghini, A.; Malatesta, P.; Campadelli-Fiume, G.; Gianni, T. αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion. Proc. Natl. Acad. Sci. 2019, 116, 20141–20150, doi:10.1073/pnas.1901931116.
  109. Hofmann, U.B.; Westphal, J.R.; Van Muijen, G.N.; Ruiter, D.J. Matrix Metalloproteinases in Human Melanoma. J. Investig. Dermatol. 2000, 115, 337–344, doi:10.1046/j.1523-1747.2000.00068.x.
  110. Sandri, S.; Faião-Flores, F.; Tiago, M.; Pennacchi, P.C.; Massaro, R.R.; Alves-Fernandes, D.K.; Berardinelli, G.N.; Evangelista, A.F.; Vazquez, V.D.L.; Reis, R.M.; et al. Vemurafenib resistance increases melanoma invasiveness and modulates the tumor microenvironment by MMP-2 upregulation. Pharmacol. Res. 2016, 111, 523–533, doi:10.1016/j.phrs.2016.07.017.
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