Systemic T Cell Immunity and T Cell Entry into Tumor Tissue

The potential of naturally induced tumor-specific effector and memory T cells to influence progression of established tumors depends on their capacity to infiltrate tumor tissues and to mediate tumor cell rejection in situ. The difficulty of this has been convincingly demonstrated in a mouse model of spontaneous insulinoma [25]. In this model, high numbers of strongly activated CTL carrying transgenic TCR with high affinity to a model foreign tumor antigen did not accumulate in the growing insulinomas and did not mediate tumor rejection. Only after activation of the tumor endothelium through inflammatory stimuli, these T cells infiltrated efficiently into the tumors and mediated tumor rejection. Interestingly, gene expression analyses revealed that strong overexpression of the transcription factor RGS5 by tumor endothelium associated pericytes might be a key regulator of the observed inhibition of T cell entry in this model [26] - a first hint that tumor endothelium not only resembles that of normal, non-inflamed tissues but that the tumor microenvironment influences the vasculature to prevent effector T cell transmigration. Another molecule, Galectin -1 is expressed by endothelial cells in tumor tissue under hypoxic conditions and mediates suppression of T cell tumor infiltration in HNSCC patients [27].

Despite these observations, numerous studies have demonstrated that tumor specific T cells can be isolated from the tumor tissues of various cancers. Among 123 tumor-infiltrating T cell (TIL) cultures from melanoma biopsies, 57% recognized HLA-A2 restricted epitopes of the highly immunogenic melanoma-associated antigens MART-1 and gp100, while much less cultures reacted to antigens presented in the context of other HLA-alleles [28]. T cell responses were frequently dominated by a single HLA allele and besides Melan-A, no dominant antigens could be characterized among a broad variety of TAAs that were simultaneously tested [29]. Multiple HLA-A2-restricted melanoma differentiation antigens were recognized by TILs from melanoma patients [30]. Interestingly, the frequencies of Mart 1-reactive HLA-A2-restricted CD8 TIL as detectable by HLA-tetramer analysis in approximately half of the freshly excised melanomas were between 1:50 and 1:200, which is similar to the frequencies of such cells in the peripheral blood [31].

Although tumor-reactive T cells may not be selectively enriched in tumor tissues, (which might as well be due to a rapid loss in situ of such cells after their encounter of cognate antigen), it may be that cognate recognition of TAAs induces their activation and subsequent effector function. In a mouse model, antigen specific CD4 and CD8 T cells eliminated not only antigen-expressing tumor cells by direct tumor cell lysis, but also antigen loss variants indirectly through destruction of the tumor supportive stromal environment. This stroma destruction was mediated by recognition of TAAs crosspresented by non malignant, bone marrow-derived stroma cells [32].

By CDR3-region analysis, PB T cell clones capable of lysing autologous ovarian carcinoma cells were detected in ovarian carcinomas [33]. In a study on colorectal carcinomas, we did not detect differences in absolute numbers of CD8 T cells between carcinoma tissue and corresponding colonic mucosa of the same patients [34]. However, TIL showed increased levels of activation as measured by CD69 expression as well as increased proportions of cells with cytotoxic degranulation in situ as measured by membrane expression of CD107a. Proportions of such TIL recognized ex vivo the colon carcinoma associated antigen MUC1 and responded with IFN-y secretion. Interestingly, the presence of functional CD4 and CD8 memory T cells with specificity for MUC1 in the bone marrow or peripheral blood of the patients was associated with increased numbers of activated or cytotoxically active CD8 TIL in colorectal carcinomas. This suggests that systemic tumor-specific immunity is a prerequisite for the presence and functional activity of tumor specific intratumoral T cells. These findings may explain in part the meanwhile well established prognostic significance of increased numbers of activated CD8 memory T cells infiltrating colorectal carcinomas [35, 36].

A recent study demonstrated in patients with multiple myeloma, demonstrated that activated bone marrow infiltrating T lymphocytes effectively targeted autologous human plasma cells and their clonogenic precursors as shown by profound inhibition in a clonogenic assay, suggesting their potential therapeutic role in situ [19]. In follicular lymphoma (FL), low numbers of CD8 TIL are a significant negative prognostic factor of overall survival [37]. Two different types of FL could be identified with regard to their composition of stroma cell infiltrates: FL1 type lymphomas contained a reactive microenvironment consisting mainly of CD8 and CD4 T cells and macrophages and were significantly associated with favorable prognosis. FL2 type lymphomas contained mainly CD57+ NK cells and were associated with a high incidence of adverse clinicobiological manifestations such as "B" symptoms. In breast canrcinomas increased T cell infiltration was correlated with lymph node negative tumor stage [38], while intraepithelial CD8 TIL and a high CD8+/regula-tory T cell ratio are associated with a favorable prognosis in ovarian cancer [39]. TIL counts in testicular seminoma and large B cell lymphoma also possessed a favorable prognostic significance [40]. Interestingly, the presence and numbers of melanoma-specific TIL but not of circulating melanoma specific T cells predicted survival in advanced stage melanoma patients [41]. Taken together, these data clearly point to a prognostic role of spontaneously induced tumor-reactive T cells in human tumors. The numbers of such cells in the tumor tissue might be gradually regulated through influences of the tumor microenvironment on the efficiency of T cell infiltration and accumulation within the tumor tissue. Besides that, the general capacity of a patient's immune system to induce functional T cell responses and to accumulate such cells in lymphoid organs such as the BM appears to be a fundamental question, since such cells are only detectable in proportions of patients.

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