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

specific signals in the microenvironment. Theoretically, it is the anti-tumor effects of
these products as well as direct interactions of the immune cells with the tumor that
should lead to its demise. In most cases, however, the tumor grows progressively
and metastasizes, largely because it evolves strategies to escape the immune intervention
and to debilitate the immune system ([13] and see below).
Among the various cells present at the tumor site, T cells have received the most attention.
This may be because some early histologic and immunohistologic studies
indicated that not only prognosis but also survival of patients with solid tumors correlated
positively with the size of the lymphocytic infiltrates [14, 15]. These infiltrates
were later shown to consist largely of CD3 + cells, which proliferated ex vivo in the
presence of interleukin (IL)-2 [16]. In fact, TIL isolated from human tumors and expanded
ex vivo in IL-2 were used for adoptive immunotherapy of patients with advanced
malignancies by Rosenberg and others [17]. The results suggested that adoptively
transferred TIL could exert anti-tumor effects, although only 15±20% of patients
with advanced cancers who received this therapy had objective clinical responses
[17]. A number of subsequent immunohistologic studies attempting to relate
the number of TIL to prognosis or survival of patients with cancer failed to
confirm the early results (reviewed in [18]). With more recent advances in methodologies
allowing not only for the phenotypic but also functional in situ analysis, characteristics
of TIL in human solid tumors became defined and the role of TIL in tumor
progression was, in part, clarified.
6.4.
Phenotypic and Functional Characteristics of Immune Cells Present at the Tumor Site
Immune cell infiltrates in the tumor microenvironment are largely composed of T
lymphocytes (reviewed in [18]). In various tumor types, macrophages, dendritic cells
(DCs) and B cells are represented with different frequencies. Characteristics of these
immune cells present at the tumor site are briefly summarized below.
6.4.1.
T Cells
6.4. Phenotypic and Functional Characteristics of Immune Cells Present at the Tumor Site
T cells [CD3 + T cell receptor (TCR) + ] found in the tumor microenvironment appear
morphologically as small lymphocytes. The hypothesis that TIL-T represent autotumor-specific
T cells has been debated for a long time and there is evidence in support
of clonal TCR Vb restriction of freshly isolated TIL as well as for their ability to recognize
autologous tumor cells in some cases [19, 20]. The phenotypic analysis of T cells
in human tumors shows that TIL-T are memory lymphocytes expressing either CD8
or CD4 markers, although the CD4/CD8 ratio may be highly variable from one tumor
to another [18]. In several studies, the CD4/CD8 ratio was found to be reduced
as a result of enrichment in CD8 + T cells [21, 22], in contrast with non-malignant inflammatory
infiltrates, which consist largely of CD4 + T cells. Furthermore, some reports
have linked a high tumor content of CD8 + T cells with a better prognosis [15],
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