Tumor infiltrating lymphocytes: The regulator of melanoma evolution (Review)

Antohe,Mihaela; Nedelcu,Roxana Ioana; Nichita,Luciana; Popp,Cristiana Gabriela; Cioplea,Mirela; Brinzea,Alice; Hodorogea,Anastasia; Calinescu,Andreea; Balaban,Mihaela; Ion,Daniela Adriana; Diaconu,Carmen; Bleotu,Coralia; Pirici,Daniel; Zurac,Sabina Andrada; Turcu,Gabriela

doi:10.3892/ol.2019.9940

Tumor infiltrating lymphocytes: The regulator of melanoma evolution (Review)

Authors:
- Mihaela Antohe
- Roxana Ioana Nedelcu
- Luciana Nichita
- Cristiana Gabriela Popp
- Mirela Cioplea
- Alice Brinzea
- Anastasia Hodorogea
- Andreea Calinescu
- Mihaela Balaban
- Daniela Adriana Ion
- Carmen Diaconu
- Coralia Bleotu
- Daniel Pirici
- Sabina Andrada Zurac
- Gabriela Turcu
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Affiliations: Department of Pathophysiology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania, Department of Pathology, Colentina Clinical Hospital, 021103 Bucharest, Romania, Department of Dermatology, Colentina Clinical Hospital, 021103 Bucharest, Romania, Department of Dermatology, Derma 360˚ Clinic, 011274 Bucharest, Romania, Department of Cellular and Molecular Pathology, ‘Stefan S. Nicolau’ Institute of Virology, 030304 Bucharest, Romania, Department of Pathology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
Published online on: January 16, 2019 https://doi.org/10.3892/ol.2019.9940
Pages: 4155-4161

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Abstract

Melanoma is the most severe type of skin cancer and its incidence has increased in the last decades. In the United States, it is the 6th most common cancer in both men and women. Prognosis for patients with melanoma depends on the stage of the disease at the time of diagnosis and it can be influenced by the immunologic response. Melanoma has been historically considered an immunogenic malignancy. It often contains great amount of immune cells (different subsets of T‑cells, dendritic cells, macrophages, neutrophils, mast cells, B lymphocytes), which may reflect a continuous intercommunication between host and tumor. It is not established if tumor-infiltrating lymphocytes (TILs) are induced by tumor cells or by other components of the microenvironment or when they are a host direct immunologic reaction. It has been observed that in many cases, the presence of a dense TIL is associated with good prognosis. The pattern and activation state of the cells which constitute TIL is variable and modulates the clinical outcome. An important step in the understanding of tumor immunobiology is the analysis of the populations and subsets of immune cells that form TIL. Besides its prognostic significance, after approval of cytotoxic T lymphocyte antigen 4, programmed cell death‑1 and programmed death‑1 ligand antibodies for the treatment of melanoma, the assessment of immune infiltrate composition has become even more captivating, as it could provide new target molecules and new biomarkers for predicting the effect of the treatment and disease outcome in patients treated with immunotherapy. In this review we discuss current state of knowledge in the field of immune cells that infiltrate melanoma, resuming the potential of TIL components to become prognostic markers for natural evolution, for response to drugs or valuable targets for new medication.

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1	Sosman JA: Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics). Atkins MB and Vora SR (eds). https://www.uptodate.com/contents/melanoma-treatment-advanced-or-metastatic-melanoma-beyond-the-basics
2	Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, Saw RP and Thompson JF: Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol. 30:2678–2683. 2012. View Article : Google Scholar : PubMed/NCBI
3	Neagu M: The immune system: A hidden treasure for biomarker discovery in cutaneous melanoma. Adv Clin Chem. 58:89–140. 2012. View Article : Google Scholar : PubMed/NCBI
4	Mukherji B: Immunology of melanoma. Clin Dermatol. 31:156–165. 2013. View Article : Google Scholar : PubMed/NCBI
5	Dummer R, Hauschild A, Lindenblatt N, Pentheroudakis G and Keilholz U: Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 26:126–132. 2015. View Article : Google Scholar : PubMed/NCBI
6	Turcu G, Nedelcu RI, Ion DA, Brînzea A, Cioplea MD, Jilaveanu LB and Zurac SA: CEACAM1: Expression and role in melanocyte transformation. Disease Markers. 2016:94063192016. View Article : Google Scholar : PubMed/NCBI
7	Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson WE, Daniels GA, DiMaio D, Ernstoff M, Fields RC, et al: Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 14:450–473. 2016. View Article : Google Scholar : PubMed/NCBI
8	Nedelcu RI, Zurac SA, Brînzea A, Cioplea MD, Turcu G, Popescu R and Ion DA: Morphological features of melanocytic tumors with depigmented halo: review of the literature and personal results. Rom J Morphol Embryol. 56:659–663. 2015.PubMed/NCBI
9	Clemente CG, Mihm Jr MC, Bufalino R, Zurrida S, Collini P and Cascinelli N: Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 77:1303–1310. 1996. View Article : Google Scholar : PubMed/NCBI
10	Clark WH, Elder DE, Guerry D, Braitman LE, Trock BJ, Schultz D, Synnestvedt M and Halpern AC: Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst Dec. 81:1893–1904. 1989. View Article : Google Scholar
11	Lee N, Zakka LR, Mihm MC and Schatton T: Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy. Pathology. 48:177–187. 2016. View Article : Google Scholar : PubMed/NCBI
12	Busam KJ, Antonescu CR, Marghoob AA, Nehal KS, Sachs DL, Shia J and Berwick M: Histologic classification of tumor-infiltrating lymphocytes in primary cutaneous malignant melanoma: A study of interobserver agreement. Am J Clin Pathol. 115:856–860. 2001. View Article : Google Scholar : PubMed/NCBI
13	Spatz A, Batist G and Eggermont AM: The biology behind prognostic factors of cutaneous melanoma. Curr Opin Oncol. 22:163–168. 2010. View Article : Google Scholar : PubMed/NCBI
14	Tuthill RJ, Unger JM, Liu PY, Flaherty LE and Sondak VK: Risk assessment in localized primary cutaneous melanoma: A southwest oncology group study evaluating nine factors and a test of the Clark logistic regression prediction model. Am J Clin Pathol. 118:504–511. 2002. View Article : Google Scholar : PubMed/NCBI
15	Elder DE, Guerry D, Vanhorn M, Hurwitz S, Zehngebot L, Goldman LI, LaRossa D, Hamilton R, Bondi EE and Clark WH Jr: The role of lymph node dissection for clinical stage I malignant melanoma of intermediate thickness (1.51–3.99 mm). Cancer. 56:413–418. 1985. View Article : Google Scholar : PubMed/NCBI
16	Hussein MR, Elsers DA, Fadel SA and Omar AE: Immunohistological characterisation of tumour infiltrating lymphocytes in melanocytic skin lesions. J Clin Pathol. 59:316–324. 2006. View Article : Google Scholar : PubMed/NCBI
17	Shurin MR, Shurin G V, Lokshin A and Ferris RL: Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies? Cancer Metast Rev. 25:333–356. 2006. View Article : Google Scholar
18	Mantovani A, Allavena P, Sica A and Balkwill F: Cancer-related inflammation. Nature. 454:436–444. 2008. View Article : Google Scholar : PubMed/NCBI
19	Van Der Bruggen P, Zhang Y, Chaux P, Stroobant V, Panichelli C, Schultz ES, Chapiro J, Van Den Eynde BJ, Brasseur F and Boon T: Tumor-specific shared antigenic peptides recognized by human T-cells. Immunol Rev. 188:51–64. 2002. View Article : Google Scholar : PubMed/NCBI
20	Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, et al: Intratumor heterogeneity and branched evolution revealed by multiegion sequencing. N Engl J Med. 366:883–892. 2012. View Article : Google Scholar : PubMed/NCBI
21	Durrant L and Ramage J: Development of cancer vaccines to activate cytotoxic T lymphocytes. Expert Opin Biol Ther. 5:555–563. 2005. View Article : Google Scholar : PubMed/NCBI
22	Ferrone S and Marincola FM: Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance. Immunol Today. 16:487–494. 1995. View Article : Google Scholar : PubMed/NCBI
23	Kageshita T, Hirai S, Ono T, Hicklin DJ and Ferrone S: Downregulation of HLA class I antigen-processing molecules in malignant melanoma. Am J Pathol. 154:745–754. 1999. View Article : Google Scholar : PubMed/NCBI
24	Al-Batran SE, Rafiyan MR, Atmaca A, Neumann A, Karbach J, Bender A, Weidmann E, Altmannsberger HM, Knuth A, et al: Intratumoral T-cell infiltrates and MHC class I expression in patients with stage IV melanoma. Cancer Res. 65:3937–3941. 2005. View Article : Google Scholar : PubMed/NCBI
25	Clancy T and Hovig E: Profiling networks of distinct immune-cells in tumors. BMC Bioinformatics. 17:1–15. 2016. View Article : Google Scholar : PubMed/NCBI
26	Schiavoni G, Gabriele L and Mattei F: The tumor microenvironment: a pitch for multiple players. Front Oncol. 3:2013.doi: 10.3389/fonc.2013.00090. View Article : Google Scholar : PubMed/NCBI
27	Tel J, Anguille S, Waterborg CEJ, Smits EL, Figdor CG and de Vries IJM: Tumoricidal activity of human dendritic cells. Trends Immunol. 35:38–46. 2014. View Article : Google Scholar : PubMed/NCBI
28	Ladányi A: Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma. Pigment Cell Melanoma Res. 28:490–500. 2015. View Article : Google Scholar : PubMed/NCBI
29	Vitale M, Cantoni C, Pietra G, Mingari MC and Moretta L: Effect of tumor cells and tumor microenvironment on NK-cell function. Eur J Immunol. 44:1582–1592. 2014. View Article : Google Scholar : PubMed/NCBI
30	Muenst S, Läubli H, Soysal SD, Zippelius A, Tzankov A and Hoeller S: The immune system and cancer evasion strategies: Therapeutic concepts. J Intern Med. 279:541–562. 2016. View Article : Google Scholar : PubMed/NCBI
31	Enk AH, Jonuleit H, Saloga J and Knop J: Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer. 73:309–316. 1997. View Article : Google Scholar : PubMed/NCBI
32	Fainaru O, Almog N, Yung CW, Nakai K, Montoya-Zavala M, Abdollahi A, D'Amato R and Ingber DE: Tumor growth and angiogenesis are dependent on the presence of immature dendritic cells. FASEB J. 24:1411–1418. 2010. View Article : Google Scholar : PubMed/NCBI
33	Da Cunha A, Michelin MA and Murta EF: Pattern response of dendritic cells in the tumor microenvironment and breast cancer. World J Clin Oncol. 5:495–502. 2014. View Article : Google Scholar : PubMed/NCBI
34	Kobayashi M, Suzuki K, Yashi M, Yuzawa M, Takayashiki N and Morita T: Tumor infiltrating dendritic cells predict treatment response to immmunotherapy in patients with metastatic renal cell carcinoma. Anticancer Res. 27:1137–1141. 2007.PubMed/NCBI
35	Simonetti O, Goteri G, Lucarini G, Rubini C, Stramazzotti D, Lo Muzio L, Biagini D and Offidani A: In melanoma changes of immature and mature dendritic cell expression correlate with tumor thickness:an immunohistochemical study. Int J Immunopathol Pharmacol. 20:325–333. 2007. View Article : Google Scholar : PubMed/NCBI
36	El Marsafy S, Bagot M, Bensussan A and Mauviel A: Dendritic cells in the skin-potential use for melanoma treatment. Pigment Cell Melanoma Res. 22:30–41. 2009. View Article : Google Scholar : PubMed/NCBI
37	Lotze MT: Getting to the source: dendritic cells as therapeutic reagents for the treatment of patients with cancer. Ann Surg. 226:1–5. 1997. View Article : Google Scholar : PubMed/NCBI
38	Boddupalli CS, Bar N, Kadaveru K, Krauthammer M, Pornputtapong N, Mai Z, Ariyan S, Narayan D, Kluger H, Deng Y, et al: Interlesional diversity of T-cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T-cells. JCI Insight. 1:e889552016.doi: 10.1172/jci.insight.88955. View Article : Google Scholar : PubMed/NCBI
39	Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ and Mor A: Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol. 153:145–152. 2014. View Article : Google Scholar : PubMed/NCBI
40	Ochsenbein AF, Klenerman P, Karrer U, Ludewig B, Pericin M, Hengartner H and Zinkernagel RM: Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci. 96:2233–2238. 1999. View Article : Google Scholar : PubMed/NCBI
41	Inman B, Frigola X, Dong H and Kwon E: Costimulation, coinhibition and cancer. Curr Cancer Drug Targets. 7:15–30. 2007. View Article : Google Scholar : PubMed/NCBI
42	Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI
43	Mapara MY and Sykes M: Tolerance and Cancer: Mechanisms of tumor evasion and strategies for breaking tolerance. J Clin Oncol. 22:1136–1151. 2004. View Article : Google Scholar : PubMed/NCBI
44	Ancuceanu R and Neagu M: Immune based therapy for melanoma. Indian J Med Res. 143:135–144. 2016. View Article : Google Scholar : PubMed/NCBI
45	Munn DH and Mellor AL: Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest. 117:1147–1154. 2007. View Article : Google Scholar : PubMed/NCBI
46	Ochoa AC, Zea AH, Hernandez C and Rodriguez PC: Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res. 13:721–726. 2007. View Article : Google Scholar
47	Becht E, Goc J, Germain C, Giraldo NA, Dieu-Nosjean MC, Sautès-Fridman C and Fridman WH: Shaping of an effective immune microenvironment to and by cancer cells. Cancer Immunol Immunother. 63:991–997. 2014. View Article : Google Scholar : PubMed/NCBI
48	Rosenberg S, Packard B, Aebersold P, Solomon D, Topalian S, Toy S, Simon P, Lotze MT, Yang JC, Seipp CA, et al: Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 319:1676–1680. 1988. View Article : Google Scholar : PubMed/NCBI
49	Cohen PJ, Lotze MT, Roberts JR, Rosenberg SA and Jaffe ES: The immunopathology of sequential tumor biopsies in patients treated with interleukin-2. Correlation of response with T-cell infiltration and HLA-DR expression. Am J Pathol. 129:208–216. 1987.PubMed/NCBI
50	Savage P, Leventhal DS and Malchow S: Shaping the repertoire of tumor-infiltrating effector and regulatory T-cells. Immunol Rev. 259:245–258. 2014. View Article : Google Scholar : PubMed/NCBI
51	Rosenberg SA and Restifo NP: Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 348:62–68. 2015. View Article : Google Scholar : PubMed/NCBI
52	Fridman WH, Remark R, Goc J, Giraldo NA, Becht E, Hammond SA, Damotte D, Dieu-Nosjean MC and Sautès-Fridman C: The immune microenvironment: A major player in human cancers. Int Arch Allergy Immunol. 164:13–26. 2014. View Article : Google Scholar : PubMed/NCBI
53	Schlapbach C, Shafighi M, Kiermeir D, Hüsler R and Hunger RE: High expression of FOXP3 in primary melanoma is associated with tumour progression. Br J Dermatol. 170:103–109. 2014. View Article : Google Scholar : PubMed/NCBI
54	Giraldo NA, Becht E, Remark R, Damotte D, Sautès-Fridman C and Fridman WH: The immune contexture of primary and metastatic human tumours. Curr Opin Immunol. 27:8–15. 2014. View Article : Google Scholar : PubMed/NCBI
55	Kiraz Y, Baran Y and Nalbant A: T-cells in tumor microenvironment. Tumor Biol. 37:39–45. 2016. View Article : Google Scholar
56	Yang ZZ and Ansell SM: The tumor microenvironment in follicular lymphoma. Clin Adv Hematol Oncol. 10:810–818. 2012.PubMed/NCBI
57	Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D and Levitsky H: The central role of CD4⁺ T-cells in the antitumor immune response. J Exp Med. 188:2357–2368. 1998. View Article : Google Scholar : PubMed/NCBI
58	Pereira MC, Oliveira DT and Kowalski LP: The role of eosinophils and eosinophil cationic protein in oral cancer (Review). Arch Oral Biol. 56:353–358. 2011. View Article : Google Scholar : PubMed/NCBI
59	Fridman WH, Pagès F, Sautès-Fridman C and Galon J: The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 12:298–306. 2012. View Article : Google Scholar : PubMed/NCBI
60	Bailey SR, Nelson MH, Himes RA, Li Z, Mehrotra S and Paulos CM: Th17 cells in cancer: the ultimate identity crisis. Front Immunol. 5:1664–3224. 2014. View Article : Google Scholar
61	Nishikawa H and Sakaguchi S: Regulatory T-cells in cancer immunotherapy. Curr Opin Immunol. 27:1–7. 2014. View Article : Google Scholar : PubMed/NCBI
62	Jiang X and Shapiro DJ: The immune system and inflammation in breast cancer. Mol Cell Endocrinol. 382:673–682. 2014. View Article : Google Scholar : PubMed/NCBI
63	Miracco C, Mourmouras V, Biagioli M, Rubegni P, Mannucci S, Monciatti I, Cosci E, Tosi P and Luzi P: Utility of tumour-infiltrating CD25⁺FOXP3⁺ regulatory T-cell evaluation in predicting local recurrence in vertical growth phase cutaneous melanoma. Oncol Rep. 18:1115–1122. 2007.PubMed/NCBI
64	Gambichler T, Bindsteiner M, Höxtermann S, Terras S and Kreuter A: Circulating CD4⁺ CD25(high) CD127(low) regulatory T-cells are an independent predictor of advanced melanoma. Pigment Cell Melanoma Res. 26:280–283. 2013. View Article : Google Scholar : PubMed/NCBI
65	Ma MW, Medicherla RC, Qian M, Vega-Saenz de Miera E, Friedman EB, Berman RS, Shapiro RL, Pavlick AC, Ott PA, Bhardwaj N, et al: Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node. Mod Pathol. 25:1000–1010. 2012. View Article : Google Scholar : PubMed/NCBI
66	Hillen F, Baeten CIM, Van De Winkel A, Creytens D, Van Der Schaft DWJ, Winnepenninckx V and Griffioen AW: Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother. 57:97–106. 2008. View Article : Google Scholar : PubMed/NCBI
67	Gooden MJM, De Bock GH, Leffers N, Daemen T and Nijman HW: The prognostic influence of tumour-infiltrating lymphocytes in cancer: A systematic review with meta-analysis. Br J Cancer. 105:93–103. 2011. View Article : Google Scholar : PubMed/NCBI
68	Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, et al: Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 520:373–377. 2015. View Article : Google Scholar : PubMed/NCBI
69	Bruno A, Ferlazzo G, Albini A and Noonan DM: A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis. J Natl Cancer Inst. 106:dju2002014. View Article : Google Scholar : PubMed/NCBI
70	Sungur CM and Murphy WJ: Positive and negative regulation by NK cells in cancer. Crit Rev Oncog. 19:57–66. 2014. View Article : Google Scholar : PubMed/NCBI
71	Balsamo M, Vermi W, Parodi M, Pietra G, Manzini C, Queirolo P, Lonardi S, Augugliaro R, Moretta A, Facchetti F, et al: Melanoma cells become resistant to NK-cell-mediated killing when exposed to NK-cell numbers compatible with NK-cell infiltration in the tumor. Eur J Immunol. 42:1833–1842. 2012. View Article : Google Scholar : PubMed/NCBI
72	Ladányi A, Kiss J, Mohos A, Somlai B, Liszkay G, Gilde K, Fejös Z, Gaudi I, Dobos J and Tímár J: Prognostic impact of B-cell density in cutaneous melanoma. Cancer Immunol Immunother. 60:1729–1738. 2011. View Article : Google Scholar : PubMed/NCBI
73	Bosisio FM, Wilmott JS, Volders N, Mercier M, Wouters J, Stas M, Blokx WA, Massi D, Thompson JF, Scolyer RA, et al: Plasma cells in primary melanoma. Prognostic significance and possible role of IgA. Mod Pathol. 29:347–358. 2016. View Article : Google Scholar : PubMed/NCBI
74	Allavena P, Sica A, Solinas G, Porta C and Mantovani A: The inflammatory micro-environment in tumor progression: The role of tumor-associated macrophages. Crit Rev Oncol/Hematol. 66:1–9. 2008. View Article : Google Scholar
75	Sica A, Schioppa T, Mantovani A and Allavena P: Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: Potential targets of anti-cancer therapy. Eur J Cancer. 42:717–727. 2006. View Article : Google Scholar : PubMed/NCBI
76	Storr SJ, Safuan S, Mitra A, Elliott F, Walker C, Vasko MJ, Ho B, Cook M, Mohammed RA, Patel PM, et al: Objective assessment of blood and lymphatic vessel invasion and association with macrophage infiltration in cutaneous melanoma. Mod Pathol. 25:493–504. 2012. View Article : Google Scholar : PubMed/NCBI
77	Mittal D, Gubin MM, Schreiber RD and Smyth MJ: New insights into cancer immunoediting and its three component phases - elimination, equilibrium and escape. Curr Opin Immunol. 27:16–25. 2014. View Article : Google Scholar : PubMed/NCBI
78	Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ and Schreiber RD: Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 450:903–907. 2007. View Article : Google Scholar : PubMed/NCBI
79	Khong HT, Wang QJ and Rosenberg SA: Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression. J Immunother. 27:184–190. 2004. View Article : Google Scholar : PubMed/NCBI
80	Maeurer MJ, Gollin SM, Martin D, Swaney W, Bryant J, Castelli C, Robbins P, Parmiani G, Storkus WJ and Lotze MT: Tumor escape from immune recognition: lethal recurrent melanoma in a patient associated with downregulation of the peptide transporter protein TAP-1 and loss of expression of the immunodominant MART-1/Melan-A antigen. J Clin Invest. 98:1633–1641. 1996. View Article : Google Scholar : PubMed/NCBI
81	Wherry EJ: T-cell exhaustion. Nat Immunol. 12:492–499. 2011. View Article : Google Scholar : PubMed/NCBI
82	Schatton T, Schütte U, Frank NY, Zhan Q, Hoerning A, Robles SC, Zhou J, Hodi FS, Spagnoli GC, Murphy GF and Frank MH: Modulation of T-cell activation by malignant melanoma initiating cells. Cancer Res. 70:697–708. 2010. View Article : Google Scholar : PubMed/NCBI
83	Solana R, Casado JG, Delgado E, DelaRosa O, Marín J, Durán E, Pawelec G and Tarazona R: Lymphocyte activation in response to melanoma: interaction of NK-associated receptors and their ligands. Cancer Immunol Immunother. 56:101–109. 2006. View Article : Google Scholar : PubMed/NCBI
84	Jandus C, Bioley G, Speiser DE and Romero P: Selective accumulation of differentiated FOXP3⁺ CD4⁺ T-cells in metastatic tumor lesions from melanoma patients compared to peripheral blood. Cancer Immunol Immunother. 57:1795–1805. 2008. View Article : Google Scholar : PubMed/NCBI
85	Gorelik L and Flavell RA: Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T-cells. Nat Med. 7:1118–1122. 2001. View Article : Google Scholar : PubMed/NCBI
86	Nicolaou A, Estdale SE, Tsatmali M, Herrero DP and Thody AJ: Prostaglandin production by melanocytic cells and the effect of α-melanocyte stimulating hormone. FEBS Lett. 570:223–226. 2004. View Article : Google Scholar : PubMed/NCBI
87	Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu G, et al: Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 65:1089–1096. 2005.PubMed/NCBI