Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

100 6 Immune Cells in the Tumor Microenvironment
although no consistent data supporting this finding had been obtained. The phenotypic
and functional characteristics of T cells found in human tumors are listed in
Tab. 6.1. In considering properties of these cells, the first striking observation was
that a vast majority of TIL-T expressed phenotypic markers of activation, i. e. were
HLA-DR + and often also CD25 + (reviewed in [18]). By this criterion, TIL-T are in the
state of activation, ready for elimination of suitable targets. However, when proliferative
and anti-tumor functions of freshly isolated TIL-T were evaluated in conventional
ex vivo assays, it appeared that they were significantly depressed compared with
equivalent functions of normal T cells [23]. The cytokine profile of these cells was
also different from that of normal activated T cells in that either no or little type 1 cytokines
[IL-2, interferon (IFN)-g] were produced by TIL-T, but instead they appeared
to preferentially secrete down-regulatory cytokines, IL-10 and transforming growth
factor (TGF)-b [24]. These data suggested that TIL-T expressing an activation phenotype
were, in fact, functionally compromised. The loss of function was not an all-ornone
phenomenon, as some TIL-Tretained substantial levels of effector cell function,
while others, particularly those isolated from advanced cancers and from metastatic
lesions, often had none. This pattern of functional defects seemed to be related to
the tumor burden and was consistent with tumor-induced immunosuppression [25].
More recent in situ studies of signaling molecules in TIL-T confirm these earlier observations
by demonstrating that expression of the TCR-associated z chain as well as
that of the transcription factor regulating expression of a number of immune and inflammatory
genes, NF-kB, is significantly decreased in TIL-T compared to their expression
in T cells obtained from the peripheral circulation of normal donors [26,
27]. In a study comprising over 130 cases of human oral cell carcinomas, expression
of z in TIL-T was found to be an independent and highly statistically significant biomarker
of prognosis and survival in patients with stage III and IV disease [28]. The
patients with tumors infiltrated by T cells with low or absent z expression had significantly
shorter 5-year survival compared to the patients with tumors infiltrated by T
cells with normal z expression [28]. Stimulus-dependent activation of NFkB was
found to be impaired in T cells of patients with renal cell carcinoma (RCC). In some
patients, the primary defect was the failure of the transactivating complex RelA/NFkB1
(p50) to accumulate in the nucleus following T cell activation due to a defect in
phosphorylation and degradation of the inhibitor IkBa [29, 30]. In other patients,
NF-kB activation was defective despite normal stimulus-dependent degradation of
IkBa [31]. In both situations, this defective state could be induced by exposure of normal
T cells to supernatants of RCC and the soluble product responsible was identified
as an RCC-derived ganglioside [31]. Impaired NF-kB activity may contribute to
reduced T cell function seen in TIL-T present in RCC, since this transcription factor
controls expression of a number of genes encoding cytokines, their receptors and
other membrane regulatory molecules essential for T cell activation [32, 33]. It is important
to note that defects in function of the z chain and activation of NF-kB are observed
in TIL-T as well as circulating T cells of patients with cancer [34, 35]. These
signaling defects in T cells are both local and systemic and may be related to the tumor
burden. Taken together, functional studies of TIL-T obtained from a variety of
human solid tumors in many different laboratories indicate that these cells are func-