Favorable outcome in clinically stage II melanoma patients is associated with the presence of activated tumor infiltrating T‐lymphocytes and preserved MHC class I antigen expression

In this study we investigated whether the presence of specific populations of tumor infiltrating lymphocytes (TILs) in diagnostic primary melanoma biopsies are related to outcome in clinically stage II melanoma patients. Moreover, we investigated whether the presence of TILs correlates with expression of MHC class I antigen and MHC class II antigen on tumor cells and/or tumor infiltrating antigen presenting cells. Diagnostic primary melanoma samples of 15 patients with an unfavorable outcome were compared with 20 patients with favorable outcome. Patients were matched for age, gender and Breslow thickness. Biopsies were examined for the presence of granzyme B+, CD8+, CD4+ and CD56+ TILs and for expression of MHC class I antigen and MHC class II antigen on tumor and/or tumor infiltrating cells. A favorable clinical outcome was strongly associated with the presence of GrB+ and CD4+ TILs, with expression of MHC class I antigen on tumor cells and with expression of MHC class II antigen on intratumoral antigen presenting cells. These data strongly support the notion that in melanoma patients the cellular immune response is a major factor in preventing melanoma cell dissemination. © 2008 Wiley‐Liss, Inc.

[1]  S. Ferrone,et al.  A fresh look at an old story: revisiting HLA class II antigen expression by melanoma cells , 2006 .

[2]  R. Schmidt,et al.  MHC-I antigen expression determines sensitivity of hematopoetic progenitor cells as targets for NK cells. , 1997, Immunobiology.

[3]  J. M. Boss,et al.  Genetic Complexity and Expression of Human Class II Histocompatibility Antigens , 1985, Immunological reviews.

[4]  S. Ferrone,et al.  HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. , 2006, Cancer research.

[5]  D L Morton,et al.  Technical details of intraoperative lymphatic mapping for early stage melanoma. , 1992, Archives of surgery.

[6]  N Cascinelli,et al.  Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  C. Balch,et al.  A Multifactorial Analysis of Melanoma: Prognostic Histopathological Features Comparing Clark's and Breslow's Staging Methods , 1978, Annals of surgery.

[8]  P. V. van Diest,et al.  The sentinel lymph node status is an important factor for predicting clinical outcome in patients with Stage I or II cutaneous melanoma , 2001, Cancer.

[9]  C. Meijer,et al.  Localization and identification of granzymes A and B‐expressing cells in normal human lymphoid tissue and peripheral blood , 1995, Clinical and experimental immunology.

[10]  D. Ruiter,et al.  MHC antigens in human melanomas. , 1991, Seminars in cancer biology.

[11]  D. Hicklin,et al.  Down-regulation of HLA class I antigen-processing molecules in malignant melanoma: association with disease progression. , 1999, The American journal of pathology.

[12]  C. Meijer,et al.  Prognostic significance of activated cytotoxic T-lymphocytes in primary nodal diffuse large B-cell lymphomas , 2004, Leukemia.

[13]  Spyros A. Kalams,et al.  The Critical Need for CD4 Help in Maintaining Effective Cytotoxic T Lymphocyte Responses , 1998, The Journal of experimental medicine.

[14]  D. Machin.  Trends in Cancer Incidence and Mortality , 1995, British Journal of Cancer.

[15]  J. D. Capra,et al.  Structure, function, and genetics of human class II molecules. , 1985, Advances in immunology.

[16]  H. Kuipers,et al.  Transcriptional regulation of antigen presentation. , 2004, Current opinion in immunology.

[17]  S. Ferrone,et al.  Association of tapasin and HLA class I antigen down-regulation in primary maxillary sinus squamous cell carcinoma lesions with reduced survival of patients. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  J. Villadangos,et al.  Presentation of antigens by MHC class II molecules: getting the most out of them. , 2001, Molecular immunology.

[19]  G. Belz,et al.  Helper T cells, dendritic cells and CTL Immunity , 2004, Immunology and cell biology.

[20]  C. Hack,et al.  The Granzyme B Inhibitor, Protease Inhibitor 9, Is Mainly Expressed by Dendritic Cells and at Immune-Privileged Sites1 , 2001, The Journal of Immunology.

[21]  Katherine S Panageas,et al.  Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  F. Marincola,et al.  Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. , 1996, Journal of the National Cancer Institute.

[23]  H. Ploegh,et al.  HLA-A- and HLA-B-specific monoclonal antibodies reactive with free heavy chains in western blots, in formalin-fixed, paraffin-embedded tissue sections and in cryo-immuno-electron microscopy. , 1990, International immunology.

[24]  S. Mian,et al.  Selective MHC expression in tumours modulates adaptive and innate antitumour responses , 1999, Cancer Immunology, Immunotherapy.

[25]  C. Gundy,et al.  Expression of the Apoptosis Inhibitor Protease Inhibitor 9 Predicts Clinical Outcome in Vaccinated Patients with Stage III and IV Melanoma , 2005, Clinical Cancer Research.

[26]  M. Bevan.  Helping the CD8+ T-cell response , 2004, Nature Reviews Immunology.

[27]  M. Plummer,et al.  International agency for research on cancer. , 2020, Archives of pathology.

[28]  R. Elashoff,et al.  Improved Long-term Survival After Lymphadenectomy of Melanoma Metastatic to Regional Nodes , 1991 .

[29]  H. Ploegh,et al.  Why certain antibodies cross-react with HLA-A and HLA-G: epitope mapping of two common MHC class I reagents. , 1998, Molecular immunology.

[30]  Gary Lyman,et al.  Age as a prognostic factor in the malignant melanoma population , 1994, Annals of Surgical Oncology.

[31]  Nathanson.  Spontaneous regression of malignant melanoma: a review of the literature on incidence, clinical features, and possible mechanisms. , 1976, National Cancer Institute monograph.

[32]  Natale Cascinelli,et al.  Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma , 1996, Cancer.

[33]  J. Lang.  Sentinel Lymph Node Tumor Load: An Independent Predictor of Additional Lymph Node Involvement and Survival in Melanoma , 2006 .

[34]  A. Streetly,et al.  Changing trends in the epidemiology of malignant melanoma: gender differences and their implications for public health. , 1995, International journal of epidemiology.

[35]  G. Ogg,et al.  Ex Vivo Staining of Metastatic Lymph Nodes by Class I Major Histocompatibility Complex Tetramers Reveals High Numbers of Antigen-experienced Tumor-specific Cytolytic T Lymphocytes , 1998, The Journal of experimental medicine.

[36]  J. Karbach,et al.  Intratumoral T-cell infiltrates and MHC class I expression in patients with stage IV melanoma. , 2005, Cancer research.

[37]  A Breslow,et al.  Thickness, Cross‐Sectional Areas and Depth of Invasion in the Prognosis of Cutaneous Melanoma , 1970, Annals of surgery.

[38]  E. Bloemena,et al.  Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients , 2006, Cancer Immunology, Immunotherapy.

[39]  L. Naldi,et al.  The epidemiology of skin cancer , 2002, The British journal of dermatology.

[40]  F. Marincola,et al.  Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance. , 1995, Immunology today.

[41]  D. Ruiter,et al.  On the biological relevance of MHC class II and B7 expression by tumour cells in melanoma metastases , 2003, British Journal of Cancer.

[42]  J. Tímár,et al.  T-Cell Activation Marker Expression on Tumor-Infiltrating Lymphocytes As Prognostic Factor in Cutaneous Malignant Melanoma , 2004, Clinical Cancer Research.

[43]  H. Gietema,et al.  Sentinel Lymph Node Tumor Load: An Independent Predictor of Additional Lymph Node Involvement and Survival in Melanoma , 2005, Annals of Surgical Oncology.

[44]  J. Baak,et al.  Analysis of major histocompatibility complex class I expression on Reed-Sternberg cells in relation to the cytotoxic T-cell response in Epstein-Barr virus-positive and -negative Hodgkin's disease. , 1996, Blood.

[45]  A. McMichael,et al.  Immune recognition of HLA molecules downmodulates CD8 expression on cytotoxic T lymphocytes , 1991, The Journal of experimental medicine.

[46]  P. Stern,et al.  Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. , 1997, Immunology today.

[47]  R. Elashoff,et al.  Improved long-term survival after lymphadenectomy of melanoma metastatic to regional nodes. Analysis of prognostic factors in 1134 patients from the John Wayne Cancer Clinic. , 1991, Annals of surgery.