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

4.3 Approaches to the Molecular Identification of (CTL)-defined Tumor Antigens
4.2
Morphological Evidence of T Cell Immunity in Human Tumors
It has been shown in animal models that infiltration of tumors by tumor-reactive T
lymphocytes is required for efficient tumor regression [4, 5]. In humans, histopathology
analysis of various types of cancers has shown that they can be infiltrated by lymphocytes,
which are routinely referred to as tumor-infiltrating lymphocytes (TILs) [6,
7]. Immunohistochemical studies in colorectal carcinomas indicated that the presence
of CD8 + T lymphocytes correlated with improved overall survival [8, 9]. Similarly,
the presence of TILs in primary melanoma lesions has also been associated
with improved prognosis [10]. In particular, it was shown that when categories of
TILs are defined as brisk (when the infiltrating lymphocytes gain access to the tumor
mass), non-brisk (peritumoral accumulations of T lymphocytes) and absent, they in
fact have strong prognostic value for primary cutaneous melanomas in the vertical
growth phase. Similar studies have also been performed in tumors from the upper
gastrointestinal tract. Analysis of infiltrating CD8 + T cells in Epstein±Barr virus
(EBV)-associated gastric cancer showed increased rates of proliferative activity and
perforin granules [11]. In three independent studies, the presence of inflammatory
cells infiltrating esophageal squamous cell carcinoma correlated positively with prognosis
[12±14]. Immunostaining of esophageal carcinomas revealing decreasing levels
of MHC class I antigen expression as compared to normal tissues was correlated to
reduced survival selectively in the squamous, but not in the adeno, cell carcinomas
[15]. In a recent report, it was shown that intratumoral CD8 + T cell infiltration more
than peritumoral infiltration was associated with a favorable clinical outcome in
both squamous cell and adenocarcinomas of the esophagus [16].
An important advance was the possibility to efficiently expand in vitro TIL populations,
recovered from enzymatically dissociated tumor masses, by culture in the presence
of high doses of IL-2. These were shown to have a more potent antitumor activity
than lymphokine-activated killer (LAK) cells in animal models of adoptive transfer
therapy [17]. Importantly, autologous TILs transferred to cancer patients persisted in
the peripheral blood for periods ranging between 6 and 60 days [18], and were able to
home to the tumor site [19]. Significant antitumor activity was observed in clinical
trials of adoptive transfer of expanded autologous TILs mainly in melanoma, but also
in other tumors such as renal cell carcinoma. These observations, coupled to the difficulties
associated with isolation, in vitro expansion and adoptive transfer of TILs, provided
the impetus at the end of the 1980s to undertake the isolation of individual tumor-reactive
Tcell clones from TILs and to identify their targets on the tumor cells.
4.3
Approaches to the Molecular Identification of Cytolytic T Lymphocyte
(CTL)-defined Tumor Antigens
The initial experimental system which allowed to unequivocally reveal the presence
of tumor-reactive T cells in humans was the so called ªmixed lymphocyte tumor cell
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