Top

Journal of Experimental & Clinical Cancer Research

Published in:

01-12-2021 | Metastasis | Research

The immune cell landscape of metastatic uveal melanoma correlates with overall survival

Authors: Anna Tosi, Rocco Cappellesso, Angelo Paolo Dei Tos, Valentina Rossi, Camillo Aliberti, Jacopo Pigozzo, Alessio Fabozzi, Marta Sbaraglia, Stella Blandamura, Paola Del Bianco, Vanna Chiarion-Sileni, Antonio Rosato

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Uveal melanoma (UM) represents the most common primary intra-ocular malignancy in adults. Up to 50% of the patients develop distant metastases within 10 years from diagnosis, with the liver as the most common site. Upon metastatization, life expectancy strongly reduces and immune checkpoint inhibitors that prove effective in cutaneous melanoma do not modify clinical outcome. To date, few studies have focused on deciphering the immunomodulatory features of metastatic UM microenvironment, and there are no prognostic models for clinical use. This highlights the urgent need to understand the delicate interplay between tumor and immune cells acting at the site of metastasis.

Methods

We collected a patient cohort comprising 21 metastatic UM patients. Hepatic and extra-hepatic UM metastasis samples were studied by multiplex immunofluorescence to assess the tumor immune cell composition. Quantitative analyses were performed to correlate immune cell densities with treatment response, metastasis site and patient survival.

Results

Compared to patients with progressive disease, those with controlled disease had a higher intra-tumoral/peritumoral ratio of CD8 + Granzyme B+ cells, higher density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL) and an increased percentage of UM cells in close proximity to T lymphocytes, reflecting a role of tumor-killing T cells in the disease. In liver metastases (LM), the intra-tumoral densities of CD163+ tumor-associated macrophages (TAM) and of total CD8+ T cells were higher than in extra-hepatic UM metastases, but the percentage of Granzyme B+ CTL was lower. Moreover, LM displayed more UM cells adjacent to both CTL and TAM, and also more T cells in proximity to TAM, all signs of an impaired immune response. The percentage of activated CTL within the tumor represented a prognostic indicator, as patients with a higher intra-tumoral percentage of CD8 + Granzyme B+ cells had the better outcome. A temptative Immunoscore was generated and proved capable to stratify patients with improved survival. Finally, CD4 + FoxP3+ T cells appeared a crucial population for response to immunotherapy.

Conclusion

The results of this study underly the clinical relevance and functional importance of composition and localization of antitumor effector cells for the progression of UM metastasis.

Available only for authorised users

Carvajal RD, Schwartz GK, Tezel T, Marr B, Francis JH, Nathan PD. Metastatic disease from uveal melanoma: treatment options and future prospects. Br J Ophthalmol. 2017;101(1):38–44. https://doi.org/10.1136/bjophthalmol-2016-309034.CrossRefPubMed

Johansson P, et al. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. Oncotarget. 2016;7(4):4624–31. https://doi.org/10.18632/oncotarget.6614.CrossRefPubMed

Akbani R, Akdemir KC, Aksoy BA, Albert M, Ally A, Amin SB, et al. Genomic classification of cutaneous melanoma. Cell. 2015;161(7):1681–96. https://doi.org/10.1016/j.cell.2015.05.044.CrossRef

Griewank KG, van de Nes J, Schilling B, Moll I, Sucker A, Kakavand H, et al. Genetic and clinico-pathologic analysis of metastatic uveal melanoma. Mod Pathol. 2014;27(2):175–83. https://doi.org/10.1038/modpathol.2013.138.CrossRefPubMed

Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology. 2011;118(9):1881–5. https://doi.org/10.1016/j.ophtha.2011.01.040.CrossRefPubMed

Willson JKV, et al. Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the collaborative ocular melanoma study (coms) coms report no. 15. Arch Ophthalmol. 2001;119(5):670–6. https://doi.org/10.1001/archopht.119.5.670.CrossRef

Lorigan JG, Wallace S, Mavligit GM. The prevalence and location of metastases from ocular melanoma: imaging study in 110 patients. Am J Roentgenol. 1991;157(6):1279–81. https://doi.org/10.2214/ajr.157.6.1950883.CrossRef

Kuk D, Shoushtari AN, Barker CA, Panageas KS, Munhoz RR, Momtaz P, et al. Prognosis of mucosal, Uveal, Acral, Nonacral cutaneous, and unknown primary melanoma from the time of first metastasis. Oncologist. 2016;21(7):848–54. https://doi.org/10.1634/theoncologist.2015-0522.CrossRefPubMedPubMedCentral

Krantz BA, Dave N, Komatsubara KM, Marr BP, Carvajal RD. Uveal melanoma: Epidemiology, etiology, and treatment of primary disease. Clin Ophthalmol. 2017;11. Dove Medical Press Ltd:279–89. https://doi.org/10.2147/OPTH.S89591.CrossRefPubMedPubMedCentral

10.

Gragoudas ES, Egan KM, Seddon JM, Glynn RJ, Walsh SM, Finn SM, et al. Survival of patents with metastases from Uveal melanoma. Ophthalmology. 1991;98(3):383–90. https://doi.org/10.1016/S0161-6420(91)32285-1.CrossRefPubMed

11.

Hsueh EC, Essner R, Foshag LJ, Ye X, Wang H-J, Morton DL. Prolonged survival after complete resection of metastases from intraocular melanoma. Cancer. 2004;100(1):122–9. https://doi.org/10.1002/cncr.11872.CrossRefPubMed

12.

Agarwala SS, Eggermont AMM, O’Day S, Zager JS. Metastatic melanoma to the liver: a contemporary and comprehensive review of surgical, systemic, and regional therapeutic options. Cancer. 2014;120(6):781–9. https://doi.org/10.1002/cncr.28480.CrossRefPubMed

13.

Chattopadhyay C, et al. Uveal melanoma: From diagnosis to treatment and the science in between. Cancer. 2016;122(15) John Wiley and Sons Inc:2299–312. https://doi.org/10.1002/cncr.29727.CrossRefPubMed

14.

Kinsey EN, Salama AKS. Metastatic uveal melanoma-A review of current therapies and future directions. Eur Oncol Haematol. 2017;13(2) Touch Briefings:100–6. https://doi.org/10.17925/OHR.2017.13.02.100.CrossRef

15.

Danielli R, Ridolfi R, Chiarion-Sileni V, Queirolo P, Testori A, Plummer R, et al. Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy. Cancer Immunol Immunother. 2012;61(1):41–8. https://doi.org/10.1007/s00262-011-1089-0.CrossRefPubMed

16.

Heppt MV, et al. Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study. J Immunother Cancer. 2019;7(1):299. https://doi.org/10.1186/s40425-019-0800-0.CrossRefPubMedPubMedCentral

17.

Chandran SS, Somerville RPT, Yang JC, Sherry RM, Klebanoff CA, Goff SL, et al. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-Centre, two-stage, single-arm, phase 2 study. Lancet Oncol. 2017;18(6):792–802. https://doi.org/10.1016/S1470-2045(17)30251-6.CrossRefPubMedPubMedCentral

18.

Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM, Nudleman E, et al. Collaborative ocular oncology group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119(8):1596–603. https://doi.org/10.1016/j.ophtha.2012.02.017.CrossRefPubMed

19.

Field MG, Decatur CL, Kurtenbach S, Gezgin G, van der Velden PA, Jager MJ, et al. PRAME as an independent biomarker for metastasis in uveal melanoma. Clin Cancer Res. 2016;22(5):1234–42. https://doi.org/10.1158/1078-0432.CCR-15-2071.CrossRefPubMedPubMedCentral

20.

Gooden MJM, De Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105(1) Nature Publishing Group:93–103. https://doi.org/10.1038/bjc.2011.189.CrossRefPubMedPubMedCentral

21.

De Cruz POL, Specht CS, McLean IW. Lymphocytic infiltration in uveal malignant melanoma. Cancer. 1990;65(1):112–5. https://doi.org/10.1002/1097-0142(19900101)65:1<112::AID-CNCR2820650123>3.0.CO;2-X.CrossRefPubMed

22.

“Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. | IOVS | ARVO Journals.” https://iovs.arvojournals.org/article.aspx?articleid=2161143 (Accessed 01 Oct 2020).

23.

Bronkhorst IHG, Ly LV, Jordanova ES, Vrolijk J, Versluis M, Luyten GPM, et al. Detection of M2-macrophages in uveal melanoma and relation with survival. Investig Ophthalmol Vis Sci. 2011;52(2):643–50. https://doi.org/10.1167/iovs.10-5979.CrossRef

24.

Krishna Y, McCarthy C, Kalirai H, Coupland SE. Inflammatory cell infiltrates in advanced metastatic uveal melanoma. Hum Pathol. 2017;66:159–66. https://doi.org/10.1016/j.humpath.2017.06.005.CrossRefPubMed

25.

Rothermel LD, Sabesan AC, Stephens DJ, Chandran SS, Paria BC, Srivastava AK, et al. Identification of an immunogenic subset of metastatic Uveal melanoma. Clin Cancer Res. 2016;22(9):2237–49. https://doi.org/10.1158/1078-0432.CCR-15-2294.CrossRefPubMed

26.

Augsburger JJ, Corrêa ZM, Shaikh AH. Effectiveness of treatments for metastatic Uveal melanoma. Am J Ophthalmol. 2009;148(1):119–27. https://doi.org/10.1016/j.ajo.2009.01.023.CrossRefPubMed

27.

Khoja L, Atenafu EG, Suciu S, Leyvraz S, Sato T, Marshall E, et al. Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol. Aug. 2019;30(8):1370–80. https://doi.org/10.1093/annonc/mdz176.CrossRefPubMed

28.

Terai M, Mastrangleo MJ, Sato T. Immunological aspect of the liver and metastatic uveal melanoma. J Cancer Metastasis Treat. 2017;3(10):231. https://doi.org/10.20517/2394-4722.2017.39.CrossRef

29.

Narducci MG, Tosi A, Frezzolini A, Scala E, Passarelli F, Bonmassar L, et al. Reduction of T lymphoma cells and immunological invigoration in a patient concurrently affected by melanoma and Sezary syndrome treated with Nivolumab. Front Immunol. 2020;11:2452. https://doi.org/10.3389/fimmu.2020.579894.CrossRef

30.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.CrossRefPubMed

31.

Wang K, Shen T, Siegal GP, Wei S. The CD4/CD8 ratio of tumor-infiltrating lymphocytes at the tumor-host interface has prognostic value in triple-negative breast cancer. Hum Pathol. 2017;69:110–7. https://doi.org/10.1016/j.humpath.2017.09.012.CrossRefPubMed

32.

Shah W, Yan X, Jing L, Zhou Y, Chen H, Wang Y. A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix. Cell Mol Immunol. 2011;8(1):59–66. https://doi.org/10.1038/cmi.2010.56.CrossRefPubMed

33.

Carstens JL, et al. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat Commun. 2017;8. https://doi.org/10.1038/ncomms15095.

34.

Neubert NJ, et al. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci Transl Med. 2018;10(436). https://doi.org/10.1126/scitranslmed.aan3311.

35.

Basile MS, et al. Immunobiology of uveal melanoma: state of the art and therapeutic targets. Front Oncol. 2019;9. Frontiers Media S.A. https://doi.org/10.3389/fonc.2019.01145.

36.

Triozzi PL, Schoenfield L, Plesec T, Saunthararajah Y, Tubbs RR, Singh AD. Molecular profiling of primary uveal melanomas with tumor-infiltrating lymphocytes. Oncoimmunology. 2019;8(10):e947169. https://doi.org/10.4161/21624011.2014.947169.CrossRefPubMed

37.

Qin Y, et al. Parallel profiling of immune infiltrate subsets in uveal melanoma versus cutaneous melanoma unveils similarities and differences: a pilot study. Oncoimmunology. 2017;6(6). https://doi.org/10.1080/2162402X.2017.1321187.

38.

Aoyama T, Mastrangelo MJ, Berd D, Nathan FE, Shields CL, Shields JA, et al. Protracted survival after resection of metastatic uveal melanoma. Cancer. 2000;89(7):1561–8. https://doi.org/10.1002/1097-0142(20001001)89:7<1561::AID-CNCR21>3.0.CO;2-R.CrossRefPubMed

39.

Qin Y, et al. Immune profiling of uveal melanoma identifies a potential signature associated with response to immunotherapy. J Immunother Cancer. 2020;8(2). https://doi.org/10.1136/jitc-2020-000960.

40.

Bao R, Surriga O, Olson DJ, Allred JB, Strand CA, Zha Y, et al. Transcriptional analysis of metastatic uveal melanoma survival nominates NRP1 as a therapeutic target. Melanoma Res. Feb. 2021;31(1):27–37. https://doi.org/10.1097/cmr.0000000000000701.CrossRefPubMed

41.

Fridman WH, Pagès F, Saut̀s-Fridman C, Galon J. The immune contexture in human tumours: Impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. https://doi.org/10.1038/nrc3245.CrossRefPubMed

42.

Cabrita R, Lauss M, Sanna A, Donia M, Skaarup Larsen M, Mitra S, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577(7791):561–5. https://doi.org/10.1038/s41586-019-1914-8.CrossRefPubMed

43.

C. Sautès-Fridman, F. Petitprez, J. Calderaro, and W. H. Fridman, “Tertiary lymphoid structures in the era of cancer immunotherapy,” Nat Rev Cancer, vol. 19, no. 6. Nature Publishing Group, pp. 307–325, Jun. 01, 2019, doi: https://doi.org/10.1038/s41568-019-0144-6.

44.

Massi D, et al. The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors. J Immunother Cancer. 2019;7(1). https://doi.org/10.1186/s40425-019-0797-4.

45.

Bronkhorst IHG, Khanh Vu TH, Jordanova ES, Luyten GPM, van der Burg SH, Jager MJ. Different subsets of tumor-infiltrating lymphocytes correlate with macrophage influx and monosomy 3 in uveal melanoma. Investig Ophthalmol Vis Sci. 2012;53(9):5370–8. https://doi.org/10.1167/iovs.11-9280.CrossRef

46.

Pagès F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391(10135):2128–39. https://doi.org/10.1016/S0140-6736(18)30789-X.CrossRefPubMed

47.

Capone M, et al. Immunoscore: a new possible approach for melanoma classification. J Immunother Cancer. Dec. 2014;2(S3):P193. https://doi.org/10.1186/2051-1426-2-s3-p193.CrossRefPubMedCentral

48.

Bifulco C, et al. MISIPI study: Melanoma ImmunoScore evaluation in patients treated with IPIlimumab. J Transl Med. 2014;12(Suppl 1):P11. https://doi.org/10.1186/1479-5876-12-s1-p11.CrossRefPubMedCentral

49.

Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006;43(2 SUPPL):1. https://doi.org/10.1002/hep.21060.CrossRef

50.

Yang M, McKay D, Pollard JW, Lewis CE. Diverse functions of macrophages in different tumor microenvironments. Cancer Res. 2018;78(19) American Association for Cancer Research Inc:5492–503. https://doi.org/10.1158/0008-5472.CAN-18-1367.CrossRefPubMedPubMedCentral

51.

Kowal J, Kornete M, Joyce JA. Re-education of macrophages as a therapeutic strategy in cancer. Immunotherapy. 2019;11(8) Future Medicine Ltd:677–89. https://doi.org/10.2217/imt-2018-0156.CrossRefPubMed

52.

Algazi AP, Tsai KK, Shoushtari AN, Munhoz RR, Eroglu Z, Piulats JM, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016;122(21):3344–53. https://doi.org/10.1002/cncr.30258.CrossRefPubMed

53.

Javed A, Arguello D, Johnston C, Gatalica Z, Terai M, Weight RM, et al. PD-L1 expression in tumor metastasis is different between uveal melanoma and cutaneous melanoma. Immunotherapy. 2017;9(16):1323–30. https://doi.org/10.2217/imt-2017-0066.CrossRefPubMed

54.

Durante MA, et al. Single-cell analysis reveals new evolutionary complexity in uveal melanoma. Nat Commun. 2020;11(1). https://doi.org/10.1038/s41467-019-14256-1.

Title: The immune cell landscape of metastatic uveal melanoma correlates with overall survival
Authors: Anna Tosi
Rocco Cappellesso
Angelo Paolo Dei Tos
Valentina Rossi
Camillo Aliberti
Jacopo Pigozzo
Alessio Fabozzi
Marta Sbaraglia
Stella Blandamura
Paola Del Bianco
Vanna Chiarion-Sileni
Antonio Rosato
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Metastasis
Melanoma
Melanoma
Choroidal Melanoma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01947-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Synthetic lethality and synergetic effect: the effective strategies for therapy of IDH-mutated cancers

The circular RNA circZFR phosphorylates Rb promoting cervical cancer progression by regulating the SSBP1/CDK2/cyclin E1 complex

SCD1, autophagy and cancer: implications for therapy

A review of the biological and clinical implications of RAS-MAPK pathway alterations in neuroblastoma

Correction to: Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway

EIF4A3-induced circ_0084615 contributes to the progression of colorectal cancer via miR-599/ONECUT2 pathway

Keynote webinar | Spotlight on antibody–drug conjugates in cancer