Tumor Evasion of the Immune System
Although the immune system clearly can respond to tumor cells, the fact that so many individuals die each year from cancer suggests that the immune response to tumor cells is often ineffective. This section describes several mechanisms by which tumor cells appear to evade the immune system.
Anti-Tumor Antibodies Can Enhance Tumor Growth
Following the discovery that antibodies could be produced to tumor-specific antigens, attempts were made to protect animals against tumor growth by active immunization with tumor antigens or by passive immunization with antitumor antibodies. Much to the surprise of the researchers, these immunizations did not protect against tumor growth; in many cases, they actually enhanced growth of the tumor.
The tumor-enhancing ability of immune sera subsequently was studied in cell-mediated lympholysis (CML) reactions in vitro. Serum taken from animals with progressive tumor growth was found to block the CML reaction, whereas serum taken from animals with regressing tumors had little or no blocking activity. K. E. and I. Hellstrom extended these findings by showing that children with progressive neuroblastoma had high levels of some kind of blocking factor in their sera and that children with regressive neuroblastoma did not have such factors. Since these first reports, blocking factors have been found to be associated with a number of human tumors.
In some cases, antitumor antibody itself acts as a blocking factor. Presumably the antibody binds to tumor-specific antigens and masks the antigens from cytotoxic T cells. In many cases, the blocking factors are not antibodies alone but rather antibodies complexed with tumor antigens. Although these immune complexes have been shown to block the CTL response,the mechanism of this inhibition is not known. The complexes also may inhibit ADCC by binding to Fc receptors on NK cells or macrophages and blocking their activity.
Antibodies Can ModulateTumor Antigens
Certain tumor-specific antigens have been observed to disappear from the surface of tumor cells in the presence of serum antibody and then to reappear after the antibody is no
longer present. This phenomenon, called antigenic modulation,is readily observed when leukemic T cells are injected into mice previously immunized with a leukemic T-cell antigen (TL antigen). These mice develop high titers of anti-TL antibody, which binds to the TL antigen on the leukemic cells and induces capping, endocytosis, and/or shedding of the antigen-antibody complex. As long as antibody is present,these leukemic T cells fail to display the TL antigen and thus cannot be eliminated.
Tumor Cells Frequently Express Low Levels of Class I MHC Molecules
Since CD8+ CTLs recognize only antigen associated with class I MHC molecules, any alteration in the expression of class I MHC molecules on tumor cells may exert a profound effect on the CTL-mediated immune response. Malignant transformation of cells is often associated with a reduction (or even a complete loss) of class I MHC molecules, and a number of tumors
have been shown to express decreased levels of class I MHC molecules. The decrease in class I MHC expression can be accompanied by progressive tumor growth,and so the absence of MHC molecules on a tumor is generally an indication of a poor prognosis.As illustrated in Figure 22-10, the immune response itself may play a role in selecting tumor cells with decreased class I MHC expression.
Tumor Cells May Provide PoorCo-Stimulatory Signals
T-cell activation requires an activating signal, triggered by recognition of a peptide–MHC molecule complex by the T-cell receptor, and a co-stimulatory signal, triggered by the interaction of B7 on antigen-presenting cells with CD28 on the T cells. Both signals are needed to induce IL-2 production and proliferation of T cells. The poor immunogenicity of many tumor cells may be due in large part to lack of the co-stimulatory molecules. Without sufficient numbers of antigen-presenting cells in the immediate vicinity of a tumor,the T cells will receive only a partial activating signal, which may lead to clonal anergy.
Cancer Immunotherapy
Although various immune responses can be generated to tumor cells, the response frequently is not sufficient to prevent tumor growth. One approach to cancer treatment is to augment or supplement these natural defense mechanisms.Several types of cancer immunotherapy in current use or under development are described in this concluding section。
Manipulation of Co-Stimulatory Signals Can Enhance Immunity
Several research groups have demonstrated that tumor immunity can be enhanced by providing the co-stimulatory signal necessary for activation of CTL precursors (CTL-Ps).When mouse CTL-Ps are incubated with melanoma cells in vitro, antigen recognition occurs, but in the absence of a costimulatory signal, the CTL-Ps do not proliferate and differentiate into effector CTLs. However, when the melanoma cells are transfected with the gene that encodes the B7 ligand,then the CTL-Ps differentiate into effector CTLs.
These findings offer the possibility that B7-transfected tumor cells might be used to induce a CTL response in vivo.For instance, when P. Linsley, L. Chen, and their colleagues injected melanoma-bearing mice with B7+ melanoma cells,the melanomas completely regressed in more than 40% of the mice. S. Townsend and J. Allison used a similar approach to vaccinate mice against malignant melanoma. Normal mice were first immunized with irradiated, B7-transfected melanoma cells and then challenged with unaltered malignant melanoma cells. The “vaccine” was found to protect a high percentage of the mice (Figure 22-11a). It is hoped that a similar vaccine might prevent metastasis after surgical removal of a primary melanoma in human patients.
Because human melanoma antigens are shared by a number of different human tumors, it might be possible to generate a panel of B7-transfected melanoma cell lines that are typed for tumor-antigen expression and for HLA expression.In this approach, the tumor antigen(s) expressed by a patient’s tumor would be determined, and then the patient would be vaccinated with an irradiated B7-transfected cell line that expresses similar tumor antigen(s).
Enhancement of APC Activity Can Modulate Tumor Immunity
Mouse dendritic cells cultured in GM-CSF and incubated with tumor fragments, then reinfused into the mice, have been shown to activate both TH cells and CTLs specific for the tumor antigens.When the mice were subsequently challenged with live tumor cells, they displayed tumor immunity.These experiments have led to a number of approaches aimed at expanding the population of antigen-presenting cells, so that these cells can activate TH cells or CTLs specific for tumor antigens.
One approach that has been tried is to transfect tumor cells with the gene encoding GM-CSF. These engineered tumor cells, when reinfused into the patient,will secrete GMCSF,enhancing the differentiation and activation of host antigen-presenting cells, especially dendritic cells. As these dendritic cells accumulate around the tumor cells, the GMCSF secreted by the tumor cells will enhance the presentation of tumor antigens to TH cells and CTLs by the dendritic cells (Figure 22-11b).
Another way to expand the dendritic-cell population is to culture dendritic cells from peripheral-blood progenitor cells in the presence of GM-CSF, TNF-_, and IL-4. These three cytokines induce the generation of large numbers of dendritic cells. There is some hope that, if these dendritic cells are pulsed with tumor fragments and then reintroduced into the patient, they can activate TH and TC cells specific for the tumor antigens. Whether these hopes are justified will be determined by further investigation.
A number of adjuvants, including the attenuated strains of Mycobacterium bovis called bacillus Calmette-Guerin (BCG) and Corynebacterium parvuum, have been used to boost tumor immunity. These adjuvants activate macrophages, increasing their expression of various cytokines, class II MHC molecules, and the B7 co-stimulatory molecule. These activated macrophages are better activators of TH cells, resulting in generalized increases in both humoral and cell-mediated responses. Thus far, adjuvants have shown only modest therapeutic results. Cytokine Therapy Can Augment Immune Responses to Tumors
The isolation and cloning of the various cytokine genes has facilitated their large-scale production. A variety of experimental and clinical approaches have been developed to use recombinant cytokines, either singly or in combination, to augment the immune response against cancer. Among the cytokines that have been evaluated in cancer immunotherapy are IFN-_, _, and _; IL-1, IL-2, IL-4, IL-5, and IL-12; GM-CSF; and TNF. Although these trials have produced occasional encouraging results, many obstacles remain to the successful use of this type of cancer immunotherapy.
The most notable obstacle is the complexity of the cytokine network itself. This complexity makes it very difficult to know precisely how intervention with a given recombinant cytokine
will affect the production of other cytokines. And since some cytokines act antagonistically, it is possible that intervention with a recombinant cytokine designed to enhance a particular
branch of the immune response may actually lead to suppression.In addition, cytokine immunotherapy is plagued by the difficulty of administering the cytokines locally. In some cases, systemic administration of high levels of a given cytokine has been shown to lead to serious and even life-threatening consequences.Although the results of several experimental and clinical trials of cytokine therapy for cancer are discussed here, it is important to keep in mind that this therapeutic approach is still in its infancy. INTERFERONS
Large quantities of purified recombinant preparations of the interferons, IFN-_, IFN-_, and IFN-_, are now available,each of which has shown some promise in the treatment of human cancer. To date, most of the clinical trials have involved IFN-_. Daily injections of recombinant IFN-_ have been shown to induce partial or complete tumor regression in some patients with hematologic malignancies such as leukemias, lymphomas, and myelomas and with solid tumors such as melanoma, Kaposi’s sarcoma, renal cancer, and breast cancer.
Interferon-mediated antitumor activity may involve several mechanisms. All three types of interferon have been shown to increase class I MHC expression on tumor cells; IFN-_ has also been shown to increase class II MHC expression on macrophages. Given the evidence for decreased levels of class I MHC molecules on malignant tumors, the interferons may act by restoring MHC expression, thereby increasing CTL activity against tumors. In addition, the interferons have been shown to inhibit cell division of both normal and malignantly transformed cells in vitro. It is possible that some of the antitumor effects of the interferons are related to this ability to directly inhibit tumor-cell proliferation. Finally, IFN-_ directly or indirectly increases the activity of TC cells, macrophages, and NK cells, all of which play a role in the immune response to tumor cells.
TUMOR NECROSIS FACTORS
In some instances, the tumor necrosis factors TNF-_ and TNF-_ have been shown to exhibit direct antitumor activity,killing some tumor cells and reducing the rate of proliferation of others while sparing normal cells (Figure 22-12). In the presence of TNF-_ or TNF-_, a tumor undergoes visible hemorrhagic necrosis and regression. TNF-_ has also been shown to inhibit tumor-induced vascularization (angiogenesis) by damaging the vascular endothelial cells in the vicinity of a tumor, thereby decreasing the flow of blood and oxygen that is necessary for progressive tumor growth IN VITRO–ACTIVATED LAK AND TIL CELLS
Animal studies have shown that lymphocytes can be activated against tumor antigens in vitro by culturing them with x-irradiated tumor cells in the presence of IL-2 and added tumor antigens. These activated lymphocytes mediate more effective tumor destruction than untreated lymphocytes when they are reinjected into the original tumor-bearing animal.It is difficult, however, to activate in vitro enough lymphocytes with antitumor specificity to be useful in cancer therapy.
While sensitizing lymphocytes to tumor antigens by this method, S.Rosenberg discovered that, in the presence of high concentrations of cloned IL-2 but without the addition of tumor antigens, large numbers of activated lymphoid cells were generated that could kill fresh tumor cells but not normal cells. He called these cells lymphokine-activated killer (LAK) cells. In one study, for example, Rosenberg found that infusion of LAK cells plus recombinant IL-2 into tumorbearing animals mediated effective tumor-cell destruction (Figure 22-13). LAK-cell populations are typically >90% activated NK cells. However, small numbers of TCR-bearing cells are present in LAK populations and it is possible that these may also contribute to their tumoricidal activity.
Because large numbers of LAK cells can be generated in vitro and because these cells are active against a wide variety of tumors, their effectiveness in human tumor immunotherapy has been evaluated in several clinical trials. In these trials,peripheral-blood lymphocytes were removed from patients with various advanced metastatic cancers and were activated in vitro to generate LAK cells. In an early study, patients were then infused with their autologous LAK cells together with IL-2. In this trial, which involved 25 patients, cancer regression was seen in some patients.
Subsequently, a more extensive trial with 222 patients resulted in complete regression in 16 patients. However, a number of undesirable side effects are associated with the high levels of IL-2 required for LAK cell activity. The most noteworthy is vascular leak syndrome,in which lymphoid cells and plasma emigrate from the peripheral blood into the tissues, leading to shock.
Tumors contain lymphocytes that have infiltrated the tumor and presumably are taking part in an antitumor response.By taking small biopsy samples of tumors, one can obtain a population of these lymphocytes and expand it in vitro with IL-2. These activated tumor-infiltrating lymphocytes are called TILs. Many TILs have a wide range of antitumor activity and appear to be indistinguishable from LAK cells. However,some TILs cells have specific cytolytic activity against their autologous tumor. These tumor-specific TILs are of interest because they have increased antitumor activity and require 100-fold lower levels of IL-2 for their activity than LAK cells do. In one study, TIL populations were expanded in vitro from biopsy samples taken from patients with malignant melanoma, renal-cell carcinoma, and small-cell lung cancer. The expanded populations of TILs were reinjected into autologous patients together with continuous infusions of recombinant IL-2. Renal-cell carcinomas and malignant melanomas showed partial regression in 29% and 23% of the patients, respectively
Monoclonal Antibodies Are Effective in Treating Some Tumors
Monoclonal antibodies have been used in various ways as experimental immunotherapeutic agents for cancer. For example,anti-idiotype monoclonal antibodies have been used with some success in treating human B-cell lymphomas and T-cell leukemias. In one remarkable study, R. Levy and his colleagues successfully treated a 64-year-old man with terminal B-cell lymphoma. At the time of treatment, the lymphoma had metastasized to the liver, spleen, bone marrow,and peripheral blood. Because this was a B-cell cancer, the membrane-bound antibody on all the cancerous cells had the same idiotype.By the procedure outlined in Figure 22-14,these researchers produced mouse monoclonal antibody specific for the B-lymphoma idiotype.When this mouse monoclonal anti-idiotype antibody was injected into the patient, it bound specifically to the B-lymphoma cells, because these cells expressed that particular idiotype. Since B-lymphoma cells are susceptible to complement-mediated lysis, the monoclonal antibody activated the complement system and lysed the lymphoma cells without harming other cells. After four injections with this anti-idiotype monoclonal antibody, the tumors began to shrink, and this patient entered an unusually long period of complete remission.
However, this approach requires that a custom monoclonal antibody be raised for each lymphoma patient. This is prohibitively expensive and cannot be used as a general therapeutic approach for the thousands of patients diagnosed each year with B lymphoma. Recently, Levy and his colleagues have used direct immunization to recruit the immune systems of patients to an attack against their B lymphoma. In a clinical trial with 41 B-cell lymphoma patients, the genes encoding the rearranged immunoglobulin genes of the lymphomas of each patient were isolated and used to encode the synthesis of recombinant immunoglobulin that bore the idiotype typical of the patient’s tumor. Each of these Igs was coupled to keyhole limpet hemocyanin (KLH), a mollusk protein that is often used as a carrier protein because of its efficient recruitment of T-cell help. The patients were immunized with their own tumor-specific antigens, the idiotypically unique immunoglobulins produced by their own lymphomas. About 50% of the patients developed anti-idiotype antibodies against their tumors. Significantly, improved clinical outcomes were seen in the 20 patients with anti-idiotype responses, but not in the others. In fact, 2 of
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