Mechanisms Underlying The Lack Of Correlation Between Clinical And Immune Responses

To date, a large number of TA-specific immunotherapy trials have been conducted in patients with malignant disease. It is clear from these studies that the various types of tumor vaccines i) have limited or no toxicity and ii) are able to induce TA-specific immune responses and/or augment already established TA-specific immune responses in immunized patients. Nevertheless, the results of these studies have highlighted two challenges facing tumor immunologists and clinical oncologists. The first is the selection of the most effective immunotherapeutic strategy, since the various available strategies have not been systematically compared. Unfortunately, this information is not likely to become available in the near future given the prohibitive costs of clinical trials. The second is the understanding of why a TA-specific T cell-based immune response, which can be detected in a variable percentage of patients, is not paralleled by a clinical response in the majority of immunized patients, despite the presence of all the necessary components for the successful development of a TA-specific immune response, i.e., TA, APC, immune effector cells and cytokines, in immunized patients. A number of mechanisms may account for the lack of correlation between immunological and clinical responses in immunized patients. They include i) qualitative and/or quantitative defects in the generation and maintenance of TA-specific immune responses and ii) changes in the antigenic profile of tumor cells because of their genetic instability.

3.1 Evidence for locoregional and systemic immune dysfunction in cancer

The presence of leukocytes in human tumors has led to speculations that these cells play a positive role in the control of tumor growth. Numerous reports in the literature have attempted to correlate the degree or type of these cellular infiltrates with prognosis and/or patient survival, without reaching a consensus (48,49). Nevertheless, 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 TIL are activated T cells containing variable proportions of CD8+ and CD4+ T cell subsets, which are almost exclusively CD45RO+ memory T cells (21,23,48,49). In comparison to autologous PBL or those isolated from tissues distant from the tumor, TIL have been consistently found to be poorly responsive or unresponsive to traditional T-cell activating stimuli (21,23,50,51) (Table 1). It has been suggested that the paucity of Th1 cytokines (i.e., IL-2, IFN-y and IL-12) at the tumor site or tumor-draining lymph node as well as the prevalence of T-reg cytokines (i.e., IL-10 or TGF-P), appear to condition evolving TA-specific T cells toward the less efficacious Th2 or T-reg functional phenotypes. In fact in patients with malignant disease, TIL have been shown to display a predominant Type-2 or/T-reg functional phenotype associated with the local production of IL-4 or IL-10 rather than the mixed Type-1/Type-2 responsiveness observed in normal donors (52). It is noteworthy that although a proportion of TIL may be anergic in vivo, they can be reactivated and polarized to Th1/Tc1-type functionality after being removed from the tumor microenvironment and appropriately stimulated in vitro in the presence of high concentrations of cytokines, especially IL-2 or IL-15 (5,7,11,53). These findings suggest that even in the face of tumor-induced immune deviation, these lymphocytes can be salvaged and may be of clinical benefit, if an appropriate treatment is administered.

Table 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 (21,23)

2. Signaling defects in TIL and PBL-T

(a) NFkB abnormalities (56,58)

(b) Ç chain defects: either low expression or absence (63,67,73,75,78)

3. Cytokine expression: absent/decreased Thl-type cytokines (103-105)

4. Inhibition of lymphocyte proliferation, cytotoxic activity or cytokine production (21,23,60)

5. Inhibition of leukocyte migration (174)

6. Induction of T-cell apoptosis (21,23,95)

7. Expansion of immunosuppressive macrophages (111,176)

Alterations in systemic TA-specific T cell immunity also occur in patients with malignant disease. In the early 1990's Mizoguchi and colleagues (54), studying dysfunctional T cells from long-term tumor bearing mice, demonstrated a marked decrease in the expression of CD3Z chain, and of p56lck as well as p59fyn tyrosine kinases, all of which play a critical role in the signal transduction events that lead to T cell activation (50). These changes were accompanied by a decreased tyrosine kinase phosphorylation and diminished calcium influx. These findings provided for the first time a molecular basis for T cell dysfunction in cancer patients. Additional studies demonstrated that T cells derived from patients with renal cell carcinoma (RCC) and from long-term tumor bearing mice were unable to translocate NFKBp65 nuclear transcription factor, resulting in a predominance of NFKBp50/50 homodimer known to act as a repressor of the IFN-y gene (55-59). In fact, cytokine production during the progressive growth of tumors in mice demonstrated a Th1 response (IL-2 and IFN-y) early after tumor implantation, followed by an increased production of Th2 cytokines (IL-4 and IL-10) after three weeks (50,60). More recent studies in patients with malignant disease confirmed these initial observations in murine models. In this regard, T cells and NK cells from approximately half of the patients with carcinoma of the head and neck (50,60,61), breast (50,60,62), stomach (50,60) colon (50,60,63,64), kidney (50,60,65,66), ovary (50,60,67), cervix (68,69) and prostate (70), as well as non-Hodgkins lymphoma (71), Hodgkins lymphoma (72), and melanoma (73,74) demonstrate a decreased CD3Z chain expression and a decreased in vitro response to antigens or mitogens. We have also demonstrated that circulating T cells are biased in their cytokine profile or otherwise functionally compromised in patients with malignant disease (60,61,75,76). Interestingly, alterations in circulating T cell function, as determined by CD3Z chain expression, proliferative index or NFkB activity, are associated with the extent of alterations in TIL function and with tumor stage (50,60,75,76). These observations suggest that CD3Z chain expression may be a marker of immune competence in patients with malignant disease and individuals who have normal CD3Z chain expression are most likely to respond favorably to biotherapy (61). It is noteworthy that changes in signal transduction molecules are not limited to CD3Z chain. Kolenko and colleagues demonstrated that Jak-3, a tyrosine kinase associated with the Y chain, a common element to IL2, IL4, IL7 and IL15 cytokine receptors, was also decreased in T cells from RCC patients (77). Moreover, T cells from RCC patients also had a diminished ability to translocate NFKBp65 (58,59). Regardless of the specific defect, the presence of such systemic alterations may explain, in part, why vaccines and other immunotherapies induce objective clinical responses in only a small minority of patients with malignant disease.

Functional defects in systemic immunity as well as TIL appear to be clinically significant. Alterations in T cell signal transduction are assocaited with advandced tumor stage in colon carcinoma (64) and RCC (57). Moreover, we have demonstrated that the level of CD3Z chain expression in TIL from patients with oral carcinoma is an independant predictive parameter of 5-year survival rate (figure 3) in patients with advanced stage disease (78). This study is the first report of a direct association between reduced CD3Z chain expression in TIL-T cells, disease progression and patient survival. It is noteworthy that abnormalities in T cell signal transduction might also occur early in disease, as diminished CD3Z chain expression has been found in patients with in situ cervical carcinoma (68,69). The role CD3Z chain defects play in the clinical course of malignant disease is highlighted by the association between CD3Z chain expression levels and response to treatment. Thus, levels of CD3Z chain expression increase in T cells of non-Hodgkins and Hodgkins lymphoma patients who respond to chemotherapy, while levels of CD3Z chain expression are reduced in patients who have recurrence of the disease (72). In addition, limited data from clinical trials in colon carcinoma, RCC, ovarian carcinoma and melanoma indicate that CD3 Z chain expression levels are increased in patients receiving IL-2 based therapies (57,74,79).

Figure 3. Association of Ç chain expression in TIL, tumor stage and lymph node involvement with survival in oral squamous cell carcinoma patients. Reduced survival is seen in patients with oral squamous cell carcinoma whose lesions demonstrate reduced Ç chain expression in TIL and (A) high tumor stage or (B) high degree of lymph node involvement. Numbers in parentheses indicate numbers of patients in each category (low Ç, stage I-II; normal Ç, stage III, low Ç, stage III-IV; and normal Ç, stage III-IV). Reproduced from ref. 71.

Figure 3. Association of Ç chain expression in TIL, tumor stage and lymph node involvement with survival in oral squamous cell carcinoma patients. Reduced survival is seen in patients with oral squamous cell carcinoma whose lesions demonstrate reduced Ç chain expression in TIL and (A) high tumor stage or (B) high degree of lymph node involvement. Numbers in parentheses indicate numbers of patients in each category (low Ç, stage I-II; normal Ç, stage III, low Ç, stage III-IV; and normal Ç, stage III-IV). Reproduced from ref. 71.

However, this did not always coincide with a full recovery of T cell function, since tyrosine kinase activity is not completely restored.

Functional impairments have also been noted for alternate effector cells that accumulate within tumor sites. Several recent reports indicate that TADCs are functionally defective, especially in their antigen-presenting capacity (80, 81). Moreover, tumor-associated macrophages (TAM) also exhibit functional defects relative to their counterparts obtained from tumor-uninvolved inflammatory sites in the same patient (81,82). However, the functional consequences of these impairments have not yet been elucidated.

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