Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 12/2011

01-12-2011 | Original article

Prognostic impact of B-cell density in cutaneous melanoma

Authors: Andrea Ladányi, Judit Kiss, Anita Mohos, Beáta Somlai, Gabriella Liszkay, Katalin Gilde, Zsuzsanna Fejős, István Gaudi, Judit Dobos, József Tímár

Published in: Cancer Immunology, Immunotherapy | Issue 12/2011

Login to get access

Abstract

Studies on the prognostic importance of tumor-infiltrating lymphocytes have mainly focused on T cells, while little is known about the role of tumor-infiltrating B lymphocytes. We investigated the prevalence of CD20+ B cells by immunohistochemistry in primary melanoma samples of 106 patients and analyzed in relation to clinicopathological parameters and patients’ survival. The majority of samples contained a significant amount of B lymphocytes, predominantly dispersed in the stroma surrounding tumor deposits (mean peritumoral and intratumoral densities: 178.7 ± 156.1 vs. 4.9 ± 6.9 cells/mm2, respectively). B cells organized in follicle-like aggregates were also observed in 26% of the samples. B-cell density correlated with that of activated (CD25+ or OX40+) T lymphocytes. Infiltration by CD20+ lymphocytes did not correlate with tumor thickness, while the presence of B-cell aggregates was observed more frequently in thick melanomas. On the other hand, B-cell infiltration was more pronounced in nonmetastatic or lymph node metastatic tumors, compared to visceral metastatic ones. Accordingly, high number of these cells provided significant survival advantage (P = 0.0391 and P = 0.0136 for intra- and peritumoral infiltration, respectively). Furthermore, combination of peritumoral B-cell density with the number of activated T lymphocytes identified patient subgroups with different disease outcome, which was most favorable in the case of high density, while very poor in the case of low density of both cell types. Multivariate survival analysis identified tumor thickness and CD20+/OX40+ cell density combination as significant independent prognostic factors. Taken together, our results show correlation between low number of CD20+ B lymphocytes and melanoma progression, indicating a possible role of tumor-infiltrating B cells in antitumoral immune response. It was also reflected in better outcome of the disease since the density of B lymphocytes alone as well as in combination with that of activated T cells proved of prognostic importance in patients with malignant melanoma.
Literature
1.
Vesalainen S, Lipponen P, Talja M, Syrjanen K (1994) Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur J Cancer 30A:1797–1803PubMedCrossRef
2.
Setälä LP, Kosma VM, Marin S, Lipponen PK, Eskelinen MJ, Syrjanen KJ, Alhava EM (1996) Prognostic factors in gastric cancer: the value of vascular invasion, mitotic rate and lymphoplasmacytic infiltration. Br J Cancer 74:766–772PubMedCrossRef
3.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohué F, Bruneval P, Cugnenc P-H, Trajanoski Z, Fridman W-H, Pagès F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964PubMedCrossRef
4.
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T (2008) Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 14:5220–5227PubMedCrossRef
5.
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, Kim WH (2008) Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 99:1704–1711PubMedCrossRef
6.
Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494PubMed
7.
Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen Y-T, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102:18538–18543PubMedCrossRef
8.
Clark WH Jr, Elder DE, Guerry D IV, Braitman LE, Trock BJ, Schultz D, Synnestvedt M, Halpern AC (1989) Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 81:1893–1904PubMedCrossRef
9.
Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N (1996) Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77:1303–1310PubMedCrossRef
10.
Barnhill RL, Fine JA, Roush GC, Berwick M (1996) Predicting five-year outcome for patients with cutaneous melanoma in a population-based study. Cancer 78:427–432PubMedCrossRef
11.
Taylor RC, Patel A, Panageas KS, Busam KJ, Brady MS (2007) Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. J Clin Oncol 25:869–875PubMedCrossRef
12.
Hillen F, Beaten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, Winnepenninckx V, Griffioen AW (2008) Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 57:97–106PubMedCrossRef
13.
Ridolfi RL, Rosen PP, Port A, Kinne D, Miké V (1977) Medullary carcinoma of the breast: a clinicopathologic study with 10 year follow-up. Cancer 40:1365–1385PubMedCrossRef
14.
Whelchel JC, Farah SE, McLean IW, Burnier MN (1993) Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. Invest Ophthalmol Vis Sci 34:2603–2606PubMed
15.
Coronella-Wood JA, Hersh EM (2003) Naturally occurring B-cell responses to breast cancer. Cancer Immunol Immunother 52:715–738PubMedCrossRef
16.
Nelson BH (2010) CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol 185:4977–4982PubMedCrossRef
17.
Hersey P, Murray E, Grace J, McCarthy WH (1985) Current research on immunopathology of melanoma: analysis of lymphocyte populations in relation to antigen expression and histological features of melanoma. Pathology 17:385–391PubMedCrossRef
18.
Ralfkaier E, Hou-Jensen K, Gatter KC, Drzewiecki KT, Mason DY (1987) Immunohistological analysis of the lymphoid infiltrate in cutaneous malignant melanomas. Virchow Arch A 410:355–361CrossRef
19.
Hussein MR, Elsers DAH, Fadel SA, Omar A-EM (2006) Immunohistological characterization of tumour infiltrating lymphocytes in melanocytic skin lesions. J Clin Pathol 59:316–324PubMedCrossRef
20.
Ladányi A, Somlai B, Gilde K, Fejös Z, Gaudi I, Tímár J (2004) T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res 10:521–530PubMedCrossRef
21.
Ladányi A, Kiss J, Somlai B, Gilde K, Fejős Z, Mohos A, Gaudi I, Tímár J (2007) Density of DC-LAMP+ mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother 56:1459–1469PubMedCrossRef
22.
Balch CM, Buzaid AC, Soong S-J, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF (2001) Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648PubMed
23.
Kiss J, Tímár J, Somlai B, Gilde K, Fejős Z, Gaudi I, Ladányi A (2007) Association of microvessel density with infiltrating cells in human cutaneous malignant melanoma. Pathol Oncol Res 13:21–31PubMedCrossRef
24.
Hansen MH, Nielsen H, Ditzel HJ (2001) The tumor-infiltrating B cell response in medullary breast cancer is oligoclonal and directed against the autoantigen actin exposed on the surface of apoptotic cancer cells. Proc Natl Acad Sci USA 98:12659–12664PubMedCrossRef
25.
O’Brien PM, Tsirimonaki E, Coomber DW, Millan DW, Davis JA, Campo MS (2001) Immunoglobulin genes expressed by B-lymphocytes infiltrating cervical carcinoma show evidence of antigen-driven selection. Cancer Immunol Immunother 50:523–532PubMedCrossRef
26.
Coronella JA, Tellemann P, Kingsbury GA, Truong TD, Hays S, Junghans RP (2001) Evidence for an antigen-driven humoral immune response in medullary ductal breast cancer. Cancer Res 61:7889–7899PubMed
27.
Coronella JA, Spier C, Welch M, Trevor KT, Stopeck AT, Villar H, Hersh EM (2002) Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. J Immunol 169:1829–1836PubMed
28.
Nzula S, Going JJ, Stott DI (2003) Antigen-driven clonal proliferation, somatic hypermutation, and selection of B lymphocytes infiltrating human ductal breast carcinomas. Cancer Res 63:3275–3280PubMed
29.
Yeilding NM, Gerstner C, Kirkwood JM (1992) Analysis of two human monoclonal antibodies against melanoma. Int J Cancer 52:967–973PubMedCrossRef
30.
Punt CJA, Barbuto JAM, Zhang H, Grimes WJ, Hatch KD, Hersh EM (1994) Anti-tumor antibody produced by human tumor-infiltrating and peripheral blood B lymphocytes. Cancer Immunol Immunother 38:225–232PubMedCrossRef
31.
Kotlan B, Simsa P, Teillaud J-L, Fridman WH, Toth J, McKnight M, Glassy MC (2005) Novel ganglioside antigen identified by B cells in human medullary breast carcinomas: the proof of principle concerning the tumor-infiltrating B lymphocytes. J Immunol 175:2278–2285PubMed
32.
Dieu-Nosjean M-C, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, Lebecque S, Fridman W-H, Cadranel J (2008) Long-term survival for patients with non–small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26:4410–4417PubMedCrossRef
33.
Suzuki A, Masuda A, Nagata H, Kameoka S, Kikawada Y, Yamakawa M, Kasajima T (2002) Mature dendritic cells make clusters with T cells in the invasive margin of colorectal carcinoma. J Pathol 196:37–43PubMedCrossRef
34.
de Visser KE, Korets LV, Coussens LM (2005) De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7:411–423PubMedCrossRef
35.
Brodt P, Gordon J (1978) Anti-tumor immunity in B lymphocyte-deprived mice. I. immunity to a chemically induced tumor. J Immunol 121:359–362PubMed
36.
Qin Z, Richter G, Schüler T, Ibe S, Cao X, Blankenstein T (1998) B cells inhibit induction of T cell-dependent tumor immunity. Nat Med 4:627–630PubMedCrossRef
37.
Shah S, Divekar AA, Hilchey SP, Cho H-M, Newman CL, Shin S-U, Nechustan H, Challita-Eid PM, Segal BM, Yi KH (2005) Increased rejection of primary tumors in mice lacking B cells: inhibition of anti-tumor CTL and TH1 cytokine responses by B cells. Int J Cancer 117:574–586PubMedCrossRef
38.
Schultz KR, Klarnet JP, Gieni RS, HayGlass KT, Greenberg PD (1990) The role of B cells for in vivo T cell responses to a Friend virus-induced leukemia. Science 249:921–923PubMedCrossRef
39.
DiLillo DJ, Yanaba K, Tedder TF (2010) B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice. J Immunol 184:4006–4016PubMedCrossRef
40.
Kaliss N (1958) Immunological enhancement of tumor homografts in mice: a review. Cancer Res 18:992–1003PubMed
41.
Salinas FA, Wee KH (1986) Prognostic and pathogenetic implications of immune complexes in human cancer. Adv Immun Cancer Ther 2:189–209PubMed
42.
Johansson M, DeNardo DG, Coussens LM (2008) Polarized immune responses differentially regulate cancer development. Immunol Rev 222:145–154PubMedCrossRef
43.
Lapointe R, Bellemare-Pelletier A, Housseau F, Thibodeau J, Hwu P (2003) CD40-stimulated B lymphocytes pulsed with tumor antigens are effective antigen-presenting cells that can generate specific T cells. Cancer Res 63:2836–2843PubMed
44.
Li Q, Grover AC, Donald EJ, Carr A, Yu J, Whitfield J, Nelson M, Takeshita N, Chang AE (2005) Simultaneous targeting of CD3 on T cells and CD40 on B or dendritic cells augments the antitumor reactivity of tumor-primed lymph node cells. J Immunol 175:1424–1432PubMed
45.
Linton P-J, Harbertson J, Bradley LM (2000) A critical role for B cells in the development of memory CD4 cells. J Immunol 165:5558–5565PubMed
46.
Rivera A, Chen CC, Ron N, Dougherty JP, Ron Y (2001) Role of B cells as antigen-presenting cells in vivo revisited: antigen-specific B cells are essential for T cell expansion in lymph nodes and for systemic T cell responses to low antigen concentrations. Int Immunol 13:1583–1593PubMedCrossRef
47.
Linton P-J, Bautista B, Biederman E, Bradley ES, Harbertson J, Kondrack RM, Padrick RC, Bradley LM (2003) Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo. J Exp Med 197:875–883PubMedCrossRef
48.
Reuschenbach M, von Knebel Doeberitz M, Wentzensen N (2009) A systematic review of humoral immune response against tumor antigens. Cancer Immunol Immunother 58:1535–1544PubMedCrossRef
49.
Milne K, Köbel M, Kalloger SE, Barnes RO, Gao D, Gilks CB, Watson PH, Nelson BH (2009) Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS One 4:e6412PubMedCrossRef
Metadata
Title
Prognostic impact of B-cell density in cutaneous melanoma
Authors
Andrea Ladányi
Judit Kiss
Anita Mohos
Beáta Somlai
Gabriella Liszkay
Katalin Gilde
Zsuzsanna Fejős
István Gaudi
Judit Dobos
József Tímár
Publication date
01-12-2011
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 12/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-011-1071-x

Other articles of this Issue 12/2011

Cancer Immunology, Immunotherapy 12/2011 Go to the issue

Original article

In vitro synthesis of primary specific anti-breast cancer antibodies by normal human peripheral blood mononuclear cells

Original article

Signals through 4-1BB inhibit T regulatory cells by blocking IL-9 production enhancing antitumor responses

Original article

A critical role for regulatory T cells in driving cytokine profiles of Th17 cells and their modulation of glioma microenvironment

Original article

Dominant responses with conservation of T-cell receptor usage in the CD8+ T-cell recognition of a cancer testis antigen peptide presented through HLA-Cw7 in patients with multiple myeloma

Original article

Ab-IL2 fusion proteins mediate NK cell immune synapse formation by polarizing CD25 to the target cell-effector cell interface

Review

Antigens in chronic myeloid leukemia: implications for vaccine development
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
Image Credits