Human Leukocyte Antigen Class I, MHC Class I Chain-Related Molecule A, and CD8+/Regulatory T-Cell Ratio: Which Variable Determines Survival of Cervical Cancer Patients?

Purpose: To investigate the effect of intraepithelial tumor-infiltrating lymphocytes (ieTIL) and their ligands expressed by cervical tumor cells on the outcome of cervical cancer patients. Experimental Design: The prognostic value of ieTILs was investigated in 115 cases of cervical cancer. T-cell subsets, CD57+ cells, and regulatory T cells (Treg) were enumerated. The associations of these different ieTIL subtypes with human leukocyte antigen (HLA) class I and MHC class I chain-related molecule A (MICA) expression were determined in relation to clinical variables and patient survival. Results: Survival analysis showed that a high number of intraepithelial Treg (FoxP3+), a low CD8+/regulatory T-cell ratio, and a weak HLA-A expression were all associated with worse survival (P = 0.034, 0.025, and 0.033, respectively, log-rank test). Further stratification of patient groups based on HLA-A-MICA expression and HLA-A-MICA-CD8+/Treg ratio revealed an even poorer survival (P = 0.005). In a multivariate Cox analysis, low CD8+/Treg ratio (P = 0.047), weak HLA-A-MICA expression (P = 0.003), and weak HLA-A-MICA expression combined with low CD8+/Treg ratio (P = 0.002) were all found to be independent unfavorable prognostic predictors in cervical carcinoma (hazard ratios, 2.7, 4.0, and 4.9, respectively). Conclusion: Weak HLA-A-MICA expression combined with low CD8+/Treg ratio reveals a patient group with the poorest survival in cervical cancer. As a single variable, low CD8+/Treg ratio was a significant independent unfavorable prognostic factor.

[1]  E. Jordanova,et al.  Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma , 2007, Cancer Immunology, Immunotherapy.

[2]  D. Focosi,et al.  CD57 expression on lymphoma microenvironment as a new prognostic marker related to immune dysfunction. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  G. Rabinovich,et al.  Immunosuppressive strategies that are mediated by tumor cells. , 2007, Annual review of immunology.

[4]  F. Garrido,et al.  MHC class I antigens and immune surveillance in transformed cells. , 2007, International review of cytology.

[5]  C. Woodman,et al.  The natural history of cervical HPV infection: unresolved issues , 2007, Nature Reviews Cancer.

[6]  Ekaterina S Jordanova,et al.  High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. , 2007, Cancer research.

[7]  F. Bray,et al.  Chapter 2: The burden of HPV-related cancers. , 2006, Vaccine.

[8]  R. Offringa,et al.  Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants , 2006, Nature Medicine.

[9]  I. Ellis,et al.  Expression of the stress‐related MHC class I chain‐related protein MICA is an indicator of good prognosis in colorectal cancer patients , 2006, International journal of cancer.

[10]  yang-xin fu,et al.  Tumor-infiltrating T lymphocytes: friends or foes? , 2006, Laboratory Investigation.

[11]  T. Oshikiri,et al.  Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma , 2006, British Journal of Cancer.

[12]  Gerd Ritter,et al.  Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  D. Chan,et al.  Risk association between human leukocyte antigen-A allele and high-risk human papillomavirus infection for cervical neoplasia in Chinese women. , 2005, The Journal of infectious diseases.

[14]  M. Schiff,et al.  HLA alleles and risk of cervical intraepithelial neoplasia among southwestern American Indian women. , 2005, Human immunology.

[15]  E. S. Tiersma,et al.  Psychosocial factors and the course of cervical intra-epithelial neoplasia: a prospective study. , 2005, Gynecologic oncology.

[16]  Cornelis J H van de Velde,et al.  Four‐color staining combining fluorescence and brightfield microscopy for simultaneous immune cell phenotyping and localization in tumor tissue sections , 2005, Microscopy research and technique.

[17]  R. Tollenaar,et al.  Natural killer cells infiltrating colorectal cancer and MHC class I expression. , 2005, Molecular immunology.

[18]  R. Leiden.  Psychosocial factors and the course of cervical intraepithelial neoplasia: A prospective study , 2005 .

[19]  D. Doherty,et al.  Characterization of NKR+ T-cell subsets in human bone marrow: implications for immunosurveillance of neoplasia. , 2005, Clinical immunology.

[20]  G. Fleuren,et al.  Prognostic relevance of TGF‐β1 and PAI‐1 in cervical cancer , 2004 .

[21]  L. Staudt,et al.  Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. , 2004, The New England journal of medicine.

[22]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[23]  R. Fisker,et al.  Leukocyte orchestration in blood and tumour tissue following interleukin-2 based immunotherapy in metastatic renal cell carcinoma , 2004, Cancer Immunology, Immunotherapy.

[24]  H. Putter,et al.  Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis , 2004, Laboratory Investigation.

[25]  E. S. Tiersma,et al.  Psychosocial factors and the grade of cervical intra-epithelial neoplasia: a semi-prospective study. , 2004, Gynecologic oncology.

[26]  D. Raulet.  Roles of the NKG2D immunoreceptor and its ligands , 2003, Nature Reviews Immunology.

[27]  S. Bellone,et al.  Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine cervix. , 2003, Gynecologic oncology.

[28]  J. Hjelmborg,et al.  Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells , 2003, Cancer Immunology, Immunotherapy.

[29]  George Coukos,et al.  Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. , 2003, The New England journal of medicine.

[30]  D. Characiejus,et al.  Predictive value of CD8highCD57+ lymphocyte subset in interferon therapy of patients with renal cell carcinoma. , 2002, Anticancer research.

[31]  Noam Brown,et al.  The role of tumour‐associated macrophages in tumour progression: implications for new anticancer therapies , 2002, The Journal of pathology.

[32]  H. Pilch,et al.  Human Papillomavirus Type 33 E7 Peptides Presented by HLA-DR*0402 to Tumor-Infiltrating T Cells in Cervical Cancer , 2000, Journal of Virology.

[33]  A. Zwinderman,et al.  Surgically-treated early cervical cancer: Prognostic factors and the significance of depth of tumor invasion. , 1999, International journal of gynecological cancer : official journal of the International Gynecological Cancer Society.

[34]  H. Chao,et al.  Lymphocyte-infiltrated FIGO Stage IIB squamous cell carcinoma of the cervix is a prominent factor for disease-free survival. , 1999, European journal of gynaecological oncology.

[35]  B. Nielsen,et al.  Quality control of immunohistochemical evaluation of tumour-associated plasminogen activators and related components. European BIOMED-1 Concerted Action on Clinical Relevance of Proteases in Tumour Invasion and Metastasis. , 1998, European journal of cancer.

[36]  L. Borysiewicz,et al.  Infiltration of cervical cancer tissue with human papillomavirus-specific cytotoxic T-lymphocytes. , 1997, Cancer research.

[37]  C. Meijer,et al.  Assessment of cytotoxic T-lymphocyte phenotype using the specific markers granzyme B and TIA-1 in cervical neoplastic lesions. , 1997, British Journal of Cancer.

[38]  G. Fleuren,et al.  Association of allele-specific HLA expression and histopathologic progression of cervical carcinoma. , 1996, Gynecologic oncology.

[39]  B. Delahunt,et al.  Infiltration By Immunocompetent Cells In Early Stage Invasive Carcinoma Of The Uterine Cervix: A prognostic study , 1996, Pathology.

[40]  G. Fleuren,et al.  Altered HLA expression by metastatic cervical carcinoma cells as a factor in impaired immune surveillance. , 1995, Gynecologic oncology.

[41]  G. Fleuren,et al.  Isolation and characterization of tumor‐infiltrating lymphocytes from cervical carcinoma , 1994, International journal of cancer.

[42]  G. Fleuren,et al.  The expression of histocompatibility-related leukocyte antigens in the pathway to cervical carcinoma. , 1994, American journal of clinical pathology.

[43]  G. Fleuren,et al.  Association between HLA-expression and infiltration of immune cells in cervical carcinoma. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[44]  J. Bodmer,et al.  Immunological paradox in testicular tumours: the presence of a large number of activated T-cells despite the complete absence of MHC antigens. , 1993, European journal of cancer.

[45]  M. Palmer,et al.  Human trophoblast and the choriocarcinoma cell line BeWo express a truncated HLA Class I molecule. , 1990, Journal of immunology.