EFFECTOR MECHANISMS IN CANCER
IMMUNITY
Immunological studies performed in animals
developing experimental tumors following exposure to MCA and other chemical
carcinogens clearly showed that the immunity directed against rejection antigens
is T-cell–mediated, since it can be transferred among mice within the same
strain through the intravenous injection of immune cells, but not through the
transfer of immune serum. Tumor-specific cytotoxic T cells (CTL) are generally
MHC-restricted CD8+ lymphocytes, because they kill target tumor
cells through recognition of an antigenic epitope bound to an appropriate MHC-I
molecule expressed on the surface of the tumor cell. Additional data suggest
that CD4+ lymphocytes are crucial to the develop-ment of CD8+
CTL.
Active CD8+ CTL can be derived from
the peripheral blood of cancer patients by propagating the cells in the
presence of interleukin-2 (IL-2) under special conditions of ap-propriate
antigenic stimulation, which over time appear to expand the CD8+
component ca-pable of expressing tumor-specific CTL activity. In extensive
studies conducted at the Surgery Branch of the National Cancer Institute, it
has been shown that tumor-infiltrating lymphocytes (TIL) obtained by expanding
lymphocyte populations present in surgically re-sected melanoma lesions often
represent an enriched population of CTL capable of recog-nizing and killing
autologous tumor cells. Taken together, these observations led to clini-cal
studies in which melanoma patients were treated by infusion of IL-2 and their
own TIL, which had been expanded ex vivo to large numbers (1011–1013).
The results of these stud-ies showed that some patients did benefit from these
experimental treatments.
Monoclonal antibodies have been extensively
utilized in studies aimed at finding out whether antibody-mediated immunity
plays any significant role in anticancer immunity. Although there is very
little evidence that antibodies are relevant to controlling tumor growth and
spread, recent laboratory and clinical studies have revealed some surprising
facts. Often cancer patients have in their serum antibodies that specifically
recognize anti-gens expressed or released by their own tumors. These antibodies
have led to the identifi-cation of several new tumor-associated antigens, and
their possible clinical relevance is currently being evaluated. Moreover,
several monoclonal antibodies are being assessed as therapeutics for a number
of human cancers, and one of them, as previously discussed, is currently approved
for treatment of breast cancers overexpressing the HER-2 gene. There-fore, it
is important to realize that, while antibodies in general may not play a major
role in natural antitumor immunity, appropriately engineered monoclonal
antibodies targeting cer-tain tumor-associated antigens may represent important
therapeutic tools against some types of cancer. The results of these clinical
studies also suggest that successful approaches to immunotherapy utilizing
either monoclonal antibodies or lymphocytes are not necessar-ily aimed at
restoring what may be defective in the host immune response of the cancer
pa-tient. What these immunotherapeutic interventions seem to achieve is the
mobilization of antitumoral immunological processes, mediated either by cells or
by proteins, to specifi-cally destroy autologous tumor cells.
Natural killer (NK) cells are a special subset
of lymphocytes capable of killing tumor cells by a less specific mechanism than
the one utilized by HLA-restricted CTL. NK cells preferentially recognize
target cells that are low or nonexpressors of MHC molecules, a phenotype
frequently exhibited by tumor cells as a way to avoid recognition by host CTL.
Activation of NK cells can be achieved in vitro by propagating and expanding
them in the presence of IL-2. These lymphokine-activated killer (LAK) cells
have been utilized in clin-ical studies similar to those using the combination
of TIL/IL-2; however, their lack of specificity supports the conclusion that
HLA-restricted CTL are the most effective killers of autologous tumor cells.
Cytokines have been intensely studied because
of their ability to modulate an exten-sive array of immune functions. We will
discuss only IL-2 and the granulocyte-macrophage colony-stimulating factor
(GM-CSF), since these two immuno-augmenting cytokines are of major importance
not only for tumor immunology, but also for immunotherapeutic ap-proaches that
have shown some real promise in recent clinical studies.
IL-2 is a well-known activator of T-cell
immunity, mostly by stimulating helper T cells to proliferate following their
interaction with antigen-presenting cells (APCs); in turn, activated helper T
cells (TH1 cells) allow for the subsequent stimulation and
proliferation of CTL, which will be ultimately responsible for destroying the
target tumor cells. The key role played by IL-2 in the activation and
maturation of the cell-mediated immune response explains to a large extent why
IL-2 has become an approved drug for immunotherapy of melanoma and renal cell
cancer. It is reasonable to expect that the uses of IL-2 may be ex-panded to
other forms of cancer and possibly to AIDS immunotherapy.
GM-CSF was identified more recently than IL-2,
and only after its discovery was it realized that one key function of this
cytokine is the activation of APCs. In a seminal study aimed at comparing the
immunogenicity of tumor cells engineered to express a wide vari-ety of
cytokines, it was shown that GM-CSF–expressing cells inactivated by irradiation
and injected as a cancer vaccine into appropriate animal hosts were able to
protect vaccinated animals from challenge with a lethal dose of unmodified
tumor cells. Moreover, it was also shown that this kind of vaccination had some
efficacy in a therapeutic setting, one in which vaccinated animals already
carried a tumor burden. The results of this work helped refocus the attention
of tumor immunologists on APCs as the central element of an effective im-mune
response. In other words, APCs appear to explain the difference between
antigenicity and immunogenicity, insofar as they could confer immunogenicity to
antigenic entities that would have otherwise been not only inef-fective, but
counterproductive to tumor immunity . These animal studies also prompted a
number of human clinical studies utilizing autologous tumor cells, either
engi-neered to produce GM-CSF or simply mixed with it, as therapeutic vaccines
for various forms of cancer.
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