Evidence for Locoregional Immune Dysfunction in Cancer

The commonly observed presence of leukocytes in human tumors has led to speculations that these cells contribute to the control of tumor growth. Despite many attempts to correlate the degree or type of cellular infiltrates with prognosis or patient survival, no consensus exists [reviewed in ref. 198], and the significance of leukocyte infiltrates in tumors remains equivocal. However, it seems reasonable to predict that it is not the presence per se, but the functional potential of the infiltrating cells confronting the tumor that determines their utility in host defense. Most tumor-infiltrating lymphocytes (TIL) are activated T cells containing variable proportions of CD8+ and CD4+ T cell subsets, which are almost exclusively CD45RO+ memory T cells [reviewed in 187, 191]. In comparison to autologous peripheral blood lymphocytes or those isolated from tissues distant from the tumor, TIL-T cells have been consistently found to be poorly responsive or unresponsive to traditional T-cell activating stimuli [197, 198]. Table 1.1 summarizes evidence accumulated to date for functional deficiencies observed in fresh TIL isolated from a wide variety of human tumors. In aggregate, these data indicate that activated T-cells derived from tumor sites or tumor-involved human lymph nodes are functionally compromised and do not behave like normal activated T cells.

Nevertheless, TIL freshly isolated from certain tumors, especially melanoma and renal cell carcinoma (RCC), are "responsive" to immunologic intervention in vitro [24]. This suggests that even in the face of tumor-induced immune deviation, these lymphocytes can be salvaged and may be of clinical benefit to the patient, if an appropriate treatment is administered. Functional impairments have also been

Table 1.1 Immune deviation in T cells present in the tumor microenvironment

1. Activation of proteolytic enzymes in tumor-infiltrating leukocytes: rapid degradation of cellular proteins [129].

2. Signaling defects in TIL and PBL-T:

(a) NFkB abnormalities [82, 172]

(b) Z chain defects: either low expression or absence [43, 72, 98, 104, 132, 211]

3. Cytokine expression: absent/decreased Th1-type cytokines [86, 128, 160].

4. Inhibition of lymphocyte proliferation, cytotoxic activity or cytokine production [29, 130, 170, 197].

5. Inhibition of leukocyte migration [121].

6. Induction of T-cell apoptosis [56, 129, 130, 190].

7. Expansion of immunosuppressive macrophages [8, 94, 95].

8. Accumulation of regulatory CD4+ CD25high T cells [6, 31, 84, 142, 146, 158]._

noted for alternate effector cells that accumulate within tumor sites. Several recent reports indicate that tumor-associated DC (TADCs) are functionally defective, especially in their antigen-presenting capacity [46]. Tumor-associated macrophages (TAMs) also exhibit functional defects relative to their counterparts obtained from tumor-uninvolved inflammatory sites in the same patient [94, 95].

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