Immunological paradox in testicular tumours: the presence of a large number of activated T-cells despite the complete absence of MHC antigens

Nouri, A. M. E.; Hussain, R.F.; Oliver, R.T.D.; Handy, A.M.; Bartkova, I.; Bodmer, Julia G.

doi:10.1016/0959-8049(93)90545-q

Cited by 33 publications

(33 citation statements)

References 24 publications

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“…Similar observations have been reported in colorectal cancer (35) and in testicular tumors (36). It has been hypothesized that these CD8 + T cells are likely to be activated through nonclassic HLA restriction elements that are also expressed on tumor cells (37) and that are recognized by CD8 + TCRah + T cells (38).…”

Section: Discussionsupporting

confidence: 68%

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?

Jordanova¹,

Gorter²,

Ayachi³

et al. 2008

Clinical Cancer Research

205

182

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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.Cervical cancer is the second most frequent cancer in women worldwide (1). The development of cervical cancer is a multistep process initiated by persistent infection with highrisk human papillomavirus (HPV; ref. 2). After high-risk HPV infection, in a limited number of patients, cervical lesions progress via cervical intraepithelial neoplasia I to cervical intraepithelial neoplasia III to cervical cancer. Cervical carcinoma cells constitutively express the HPV-encoded E6 and E7 oncoproteins. Therefore, peptides derived from these viral antigens can be generated and presented in the context of human leukocyte antigen (HLA) class I to cytotoxic T cells. The presence of substantial numbers of lymphocytes in cervical carcinomas as previously reported by our group and others suggests the presence of a cellular antitumor response (3 -6). Indeed, HPV-specific CD4 + and CD8 + T cells can be isolated from cervical tumors and CD8 + T-cell clones are able to kill cervical cancer cells in vitro (7 -10). However, this does not seem to be sufficient to eradicate the tumor. During tumor development, cancer cells have acquired several strategies to avoid eradication by cytotoxic T cells and natural killer (NK) cells. Among these mechanisms are down-regulation of HLA class I, down-regulation of MHC class I chain-related molecule A (MICA; a cytotoxic T-cell and NK cell ligand), production of immunosuppressive cytokines such as transforming growth factor-h, and the induction of i...

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Section: Discussionsupporting

confidence: 68%

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?

Jordanova¹,

Gorter²,

Ayachi³

et al. 2008

Clinical Cancer Research

205

182

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“…The differentiating round spermatids expressing the Smage genes are located in the adluminal compartment of the seminiferous tubule, which is isolated from the vascular system by the Sertoli cell barrier (Russel et al 1990). In addition, differentiating germ cells do not express presenting class I molecules, since HLA transcripts are only detected at low levels in stem cells of the basal compartment (Janitz et al 1993), and since this region is only stained by a monoclonal antibody detecting free heavy chains (Nouri et al 1993). It has of course to be confirmed that the MAGE-Xq mRNA distribution in testis is similar to the one described here for the Smage genes.…”

supporting

confidence: 56%

The SMAGE gene family is expressed in post-meiotic spermatids during mouse germ cell differentiation

et al. 1995

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The human melanoma cell line MZ2-MEL expresses several tumor antigens defined in vitro by autologous cytolytic T lymphocytes (H~rin et al. 1987). One of these antigens, MZ2-E, has been identified as a nonapeptide encoded by the MAGE1 gene and presented at the tumor cell surface by the HLA-A1 molecule (van der Bruggen et al. 199t). Gene MAGEI belongs to a family of closely related genes . The MAGE genes are clustered within two distinct regions on chromosome X. MAGE1 to -12 are located in the q terminal region of the chromosome (Xq26-qter), while an additional member (MAGE-Xp) has been identified in the Xp21.3 locus (Muscatelli et al. 1995). The MAGE gene family is silent in healthy adult tissues, with two important exceptions: testis, where all members but MAGE7 are expressed, and placenta, where transcripts for MAGE3 and -4 have been detected. In contrast, MAGEI, -2, -3, -4, -6, and -12 are frequently expressed at high levels in a significant proportion of tumors of various histological types, including melanomas, colon carcinomas, leukemias, lung cancers, sarcomas, and breast cancers . In addition to the peptide corresponding to antigen MZ2-E, an additional peptide derived from MAGE1 ) and a peptide derived from MAGE3 (Gaugler et al. 1994) have recently been identified as tumor antigens recognized by autologous cytolytic T cells. The MAGE proteins are therefore considered to be attractive targets for cancer immunotherapy. However, it remains to be demonstrated that such a therapy will not affect tissues, like testis, where the corresponding genes are expressed.

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“…2,3,19,20 By immunohistochemistry, we were not able to detect Class I expression on the seminoma cells in the analyzed lesions. However, immunohistochemistry is low resolution, and it cannot be excluded that seminoma cells express Class I molecules at a level sufficient for T-cell recognition.…”

Section: Discussionmentioning

confidence: 86%

“…1 Seminomas are characterized by a prominent infiltration of lymphocytes with increased numbers of CD8 T cells when compared to the surrounding tissue and the peripheral blood. [2][3][4] In other cancers, e.g. malignant melanoma and ovarian cancer, a brisk infiltration of T cells are of prognostic significance 5,6 ; and recently, a strong correlation between low numbers of tumor infiltrating lymphocytes (TILs) and increased risk of relapse was demonstrated in stage I seminomas.…”

mentioning

confidence: 99%

Tumor infiltrating lymphocytes in seminoma lesions comprise clonally expanded cytotoxic T cells

Hadrup

Brændstrup

Jacobsen

et al. 2006

Intl Journal of Cancer

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Seminoma lesions are characterized by a brisk inflammatory infiltrate containing both CD4 and CD8 T cells, which is of prognostic significance. However, whether seminoma cells express the HLA molecules required for classical T-cell recognition remains controversial. In the present study, we conducted a molecular, phenotypical and functional characterization of tumor infiltrating lymphocytes (TILs) from seminoma lesions. T-cell receptor clonotype mapping demonstrated the presence of clonally expanded T cells in the majority of the lesions. The cytotoxic capacity of TILs was indicated by expression of CD107a, which is a recently described surrogate marker for cytolytic activity. Indeed, the frequency of CD107a positive cells was substantially higher in TILs when compared to peripheral blood mononuclear cells. Moreover, fluorescence activated cell sorting of CD107a positive TILs allowed comparison of the clonotypic T-cell receptor fingerprint and demonstrated the ability of expanded clones to express this cytotoxic marker, suggesting cytotoxic activity at the tumor site. The cytotoxicity was confirmed by in situ granzyme B expression. Furthermore, by staining with multimeric HLA-peptide complexes, we could demonstrate the presence of Mage-3 specific T cells among TILs. In summary, specific and functional T-cell responses are operative in seminoma, indicating that the inflammatory infiltrate is indeed involved in the immunological control of the tumor. ' 2006 Wiley-Liss, Inc.

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Immunological paradox in testicular tumours: the presence of a large number of activated T-cells despite the complete absence of MHC antigens

Cited by 33 publications

References 24 publications

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?

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?

The SMAGE gene family is expressed in post-meiotic spermatids during mouse germ cell differentiation

Tumor infiltrating lymphocytes in seminoma lesions comprise clonally expanded cytotoxic T cells

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