Biologic Significance of Locoregional Immune Suppression

Functional defects in TIL appear to be biologically significant. For example, we have documented the presence of signaling defects in T cells isolated from tumor biopsies of 138 patients with oral carcinoma [132]. We evaluated the expression of the CD3Z chain in TIL, using semiquantitative analysis of immunostained sections of paraffin-embedded tumors [132]. TIL were scored as negative/weakly stained (0 or 1) or as positive (2) for Z expression. The results showed that 32% of tumors had absent or low expression of Z in TIL, and that this alteration was significantly associated with an advanced stage (T3 or T4) as well as nodal involvement [132]. In oral carcinoma patients with advanced disease, normal expression of Z in TIL was predictive of a significantly better 5-year survival (Fig. 1.1) and was independent of other established prognostic parameters [132]. This report of a direct association between reduced Z expression in TIL-T cells, disease progression and overall patient survival suggested that functional abnormalities observed in TIL have important biologic consequences. It has been also reported that decreased expression of Z occurs in patient peripheral blood mononuclear cells (PBMC) [72, 131]. These observations suggest that in patients with cancer, Z may be a marker of

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Fig. 1.1 (A), Kaplan-Meier plots presenting survival of patients with oral SCC by Z chain expression in TIL and by tumor stage. Numbers in parentheses, numbers of patients in each category (low Z, stage I—II; normal Z, stage I—II, low Z, stage III-IV; and normal Z, stage III-IV). (B), Kaplan-Meier plots presenting survival of patients with oral SCC by lymph node involvement and low or normal Z chain expression in TIL

immune competence, and individuals who have normal Z expression are most likely to respond favorably to biotherapy [195].

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