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

Abstract

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.

Programmed Death (PD)-1:PD-Ligand 1/PD-Ligand 2 Pathway Inhibits T Cell Effector Functions during Human Tuberculosis

“…Our data clearly support that the PD-1: PD-Ls interactions function as an inhibitory pathway on the lytic degranulation of Ag-specific CD8 ϩ T cells against M. tuberculosis, as illustrated by acquisition of CD107a/b expression. Given that the expression of CD107a/b has been described as a surrogate marker for cytolytic activity (18,54,55), we conclude that the PD-1 pathway would inhibit the cytotoxic activity against the pathogen. Accordingly, several groups have demonstrated that blocking PD-1:PD-Ls interactions in vitro reverses the exhaustion of HIV and hepatitis C virus-specific CD8 ϩ and CD4 ϩ T cells and restores cytokine production and proliferation (36, 38, 56, 57).…”

Germ Cell Tumors of the Ovary: An Update

“…Large, clear, neoplastic, primitive-type germ cells are consistently associated with a variable cytotoxic Tcell lymphocytic response 20 that helps to identify the tumor, even in cases with complex histology. Adequate fixation is important for a prima facie diagnosis, but often poor fixation destroys highly labile cells owing to a minimal amount of cytoskeletal fibrils.…”

Vascular Endothelial Growth Factor and Its Relationship to Inflammatory Mediators

“…Atiprimod {2-(3-diethylaminopropyl)-8,8-dipropyl-2-azaspiro [4,5] decane dimaleate} has anti-inflammatory activities in animal models of rheumatoid arthritis and is well tolerated in phase I trials (61). Atiprimod also inhibits the proliferation of multiple myeloma cell lines in vitro by inhibiting signal transducer and activator of transcription 3 activation, thereby blocking the signaling pathway of IL-6, an important growth factor for multiple myeloma (62).…”

“…Chronic inflammation can be caused by infection, autoimmune disease, malignant and benign tumors, or other pathologies and results in the infiltration of inflammatory cells at specific sites in the body. These so-called tumor-infiltrating lymphocytes include macrophages (3), T cells, B cells, natural killer cells, neutrophils, and granulocytes (4,5). These cells excrete copious amounts of inflammatory cytokines into the microenvironment, including interleukin-6 (IL-6), IL-1a, IL-1h, tumor necrosis factor-a, and oncostatin M. For example, T lymphocytes and macrophages are the predominant inflammatory cells present in malignant prostate epithelium (4).…”