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Although various methods of immune stimulation have been attempted for treatment of thoracic malignancies, none have proven to be reliably effective (1). In contrast, immune-based therapies have proven more successful in melanoma and renal cell carcinoma (4, 5), leading to the misconception that thoracic malignancies are nonimmunogenic and will not be amenable to immunologic interventions. In ground-breaking studies, however, Boon and colleagues found that protective immunity can be generated against nonimmunogenic murine tumors (6, 7). These studies suggest that a tumor's apparent lack of immunogenicity is indicative of a failure to elicit an effective host response rather than a lack of tumor antigen expression (8, 9). Accordingly, a new paradigm emerged that focused on generating antitumor responses by therapeutic vaccination (10, 11). In this setting, vaccination refers to an intervention that unmasks tumor antigens leading to generation of specific host-immune responses against the tumor.
Several techniques have been used to detect tumor antigens (Ags) that are recognized by humoral and/or cellular
immune responses. In this issue of the Red Journal, Robinson and colleagues report results using a technique referred
to as "serologic analysis of recombinant complementary
DNA (cDNA) expression libraries," or SEREX, to identify
tumor antigens (12). This technique identifies antibody responses generated in patients with malignant mesothelioma (MM) by using sera from the patients to interact with tumor
cDNA libraries to identify specific Ags. Of particular interest is the finding of antibodies to topoisomerase II
in 13 of
14 patients with MM. The discovery of shared tumor antigens in patients with MM may have implications for both
the diagnosis and eventual immune targeting of this disease,
and these authors are applauded for initiating this process.
In addition, Robinson and associates found that the number
of serum reactivities correlated with patient survival, but
the significance of this observation will require further
study. In contrast to the use of cloned cell lines used in their
study, the SEREX technique is most often applied with fresh tumors to avoid potential in vitro artifacts. And although SEREX is a powerful method to search for tumor
antigens, certain caveats should be noted. For example, antigenic epitopes that undergo conformational changes when
expressed in bacteria will not be detected (12). Similarly,
glycosylated epitopes will escape detection. Modifications
of the SEREX method are currently being developed to
identify particular classes of antigens (13).
Although tumor reactive antibodies have been reported to have a high frequency in patients with cancer, these antibodies have not always correlated with disease activity or effective immunity (14). For example, Qin and coworkers found that diminished tumor immunogenicity could be caused by nonprotective humoral responses that disable CD4 help for cytotoxic T lymphocyte (CTL)- mediated tumor immunity (15). Thus, B-cell responses may actually inhibit induction of T-cell-dependent immunity, and studies have suggested that antibodies could have a tolerogenic effect on protein Ag (16). In contrast, other studies suggest that humoral tumor antigens can function as rejection antigens. The evidence for this includes antitumor responses in experimental models after monoclonal antibody therapy (20) and the intriguing observation that serum antibodies against p53 correlated with both improved survival and limited stage in lung cancer patients (21).
The SEREX approach has now been used to define many epitopes, and some of these may be important in thoracic malignancies (22, 23). The largest number are serologically defined antigens that correspond to previously unknown genes. Other epitopes identified by SEREX have been previously identified as tumor antigens recognized by CTL. NY-ESO-1 is a SEREX-defined antigen originally found in esophageal carcinoma and subsequently noted to be recognized by CTL in lung cancer (22, 24). Thus, NY-ESO-1 has been suggested as a potential target for lung cancer immunotherapy (24). Tumor antigens originally defined by T-cell responses have also been noted in SEREX evaluation. These include members of the melanoma antigen (MAGE) family, including MAGE-3, which has been noted to be expressed by lung cancers (25, 26). Thus, these findings are evidence of a complex host response to tumor antigens and raise the possibility that those epitopes identified by both serologic and CTL methods may have the potential to be used clinically to exploit this interplay.
Most investigations in this field have sought to identify Ags capable of eliciting a T-cell-mediated immune response (27). The majority of these tumor antigens is detected by first transfecting either genomic DNA or cDNA libraries into cells expressing the appropriate major histocompatibilty complex (MHC) phenotype, and then using antitumor CTL to identify specificity against the transfectants (28). A second technique to identify tumor antigens includes in vitro sensitization of T cells to candidate antigens. These T-cell clones are then assessed for their capacity to respond to tumor cells by either specific release of cytokines or cytolytic activity (28). A third and technically difficult technique is the elutriation of tumor peptides from tumor cells with subsequent assessment of the peptides for their capacity to stimulate CTL (29). In all of these techniques, the critical step is recognition of T-cell responses against antigenic epitopes.
Tumor antigens recognized by T cells can be categorized into four general groups (30). Type I antigens result from somatic mutations in normal gene products. Examples are the point mutations in connexin 37 discovered in Lewis lung carcinoma by Mandelboim and colleagues (31). These peptides, termed MUT1 and MUT2, can be used in lung cancer models to immunize and protect mice against tumor challenge, as well as mediate regression of established lung cancer (32). Type II antigens are those resulting from mutated oncogenes, although it is proposed that the likelihood of a mutation generating an immunodominant epitope is a rare event (35). For example, p53 has been shown to generate CTL responses in lung cancer (36); however, it is not yet known whether these mutations can generate effective, protective immunity. In addition, viral antigens expressed by tumors thought to be of viral origin can also be included among the Type II antigens. Although SV40 proteins have been detected in MM, the role of these proteins in the pathogenesis of this malignancy remains controversial. Waheed and associates (37) recently showed that antisense to SV40 early gene regions induced growth arrest and apoptosis in SV40 T-antigen positive MM. The actual significance of these provocative findings awaits further evaluation. Type III antigens are normal gene products having restricted tissue distribution. These antigens include the MAGE and GAGE antigen families that were initially defined in melanoma, and several of these antigens are expressed in lung cancers (38- 40). Type IV antigens have been referred to as "differentiation antigens" and consist of normal tissue-specific gene products. These antigens have been discovered in melanoma and include tyrosinase and MART-1 (26).
There is good evidence to suggest that tumor antigens recognized by CTL play pivotal roles in tumor rejection (41). CTL have the capacity to discriminate subtle changes in antigens expressed by the MHC class I pathway. Acting in concert with CTL, CD4+ T cells function to induce and extend the CTL response by producing cytokines requisite for a fully functional cell-mediated response (35). CD4 cells may also be responsible for recognition of MHC class II-dependent epitopes (42). However, not all tumor-associated antigens recognized by CTL serve as tumor rejection antigens (30). The most prevalent tumor antigens recognized by T cells are actually self-antigens (43), suggesting that tumor immunity may be viewed as a form of autoimmunity (44). The clinical manifestations of the theory linking tumor immunity and autoimmunity are best exemplified in melanoma; patients who develop vitiligo have a better prognosis and are more likely to respond to therapy (45). Similarly, in vivo tumor model systems have shown that immunotherapy directed against tumor antigens can induce autoimmune disease (46, 47). However, autoimmunity is not a prerequisite because effective tumor reduction can be achieved when tumor immunity and autoimmunity are uncoupled (44).
Despite the identification of a repertoire of tumor antigens, hurdles persist in the pathway to finding successful immune-based therapies. First, an immune response to a malignancy may not develop as a result of tolerance (48). It has been suggested that the single most important determinant of tumor rejection antigen potency is the avidity of the cognate CTL (49). The tolerogenic response appears to eliminate high-avidity T cells but spares the low-avidity CTL effector populations (50). Thus, the most effective cancer immunotherapies may be those interventions that significantly activate the low-avidity T-cell populations. A second major problem, well documented in thoracic and other malignancies, is the active immune suppression induced by the tumor itself (48). Tumor-reactive T cells have been shown to accumulate in lung cancer tissues but fail to respond because of suppressive tumor cell-derived factors (51). Moreover, tumor cells may also direct surrounding inflammatory cells to release suppressive cytokines in the tumor milieu (52, 53). For example, tumor-derived prostaglandin (PG)E2 has been documented to orchestrate an imbalance in the production of suppressive- and immune-potentiating cytokines by lymphocytes and macrophages in the tumor environment (52). Specifically, tumor-derived PGE2 can upregulate the transcriptional rate of interleukin (IL)-10 in human lymphocytes (52), which leads to a decrement in the activities of both T cells and antigen-presenting cells (APC) in the tumor-bearing host (34). Importantly, effective antitumor responses can be restored through abrogation of tumor PGE2 production (54).
Lung cancer cells also have defects in antigen processing and diminished MHC expression (55, 56), rendering them ineffective as APC. Thus, as defined in elegant studies by Huang and colleagues (57), professional APC play a major role in the immune response against cancer. This has led to the recent emphasis on the use of professional APC as the major source of tumor antigen presentation in vivo in genetic immunotherapies. Dendritic cells (DC) are highly specialized professional APC with the potent capacity to capture, process, and present antigen to T cells (58). Unfortunately, tumor cells interfere with host DC maturation and function (59, 60). To circumvent the in vivo inhibition of DC maturation and function, protocols have been developed that enable DC to undergo cytokine-stimulated maturation ex vivo. These cells can then be used to generate antigen-specific CTL responses in a variety of models, as well as in clinical trials (33, 61). In this context, delivery of tumor antigens by ex vivo-stimulated DC may be superior to purified peptides in avoiding CTL tolerization (68), and vaccination with multiple tumor antigens may be superior to the use of a single epitope (68, 69). Thus, another method of exposing the DC to a wide array of tumor antigens is the administration of DC intratumorally after ex vivo maturation. Introducing immune-potentiating cytokine genes into these DC further enhances the antitumor response. For example, intratumorally administered, cytokine gene-modified DC were found to take up antigen at the tumor site, traffick to regional and systemic lymph nodes, and generate systemic antitumor responses and long-term immunity (70). Intratumoral therapy with cytokine gene-modified DC yielded systemic antitumor effects comparable to those achieved with specific tumor-antigen-pulsed DC. This finding may have important implications in human lung cancer, where at this time, specific tumor antigen-based therapies are difficult to achieve (11). Although additional specific tumor antigens may be identified, immunization with individual peptides may contribute to tolerance (68). Peptide-induced tolerization of CTL has resulted in the inability of animals to reject antigen-expressing tumors (68), and strong evidence has been presented for immunoselection of antigen-loss variants in human cancer (5, 71). These limitations could be circumvented by the use of intratumoral DC- based genetic immunotherapies in which the tumor provides an array of immunogenic epitopes in situ. The effective use of activated DC administered intratumorally without antigen pulsing ex vivo implies that cross-presentation, the MHC class I-restricted presentation of exogenous antigens leading to CD8+ T-cell responses (72), is operative. In fact, DC have been implicated as the APC predominantly effective in cross-presentation (73). In accord with these findings, novel tumor antigen delivery systems using cytokine gene-transduced tumor cells and DC (61, 64) or fusion of tumor cells with DC have resulted in induction of antitumor immunity (74, 75). A recent clinical study in which tumor cell-dendritic cell hybrids were administered to 17 patients with metastatic renal cell carcinoma resulted in seven antitumor responses, including four complete antitumor responses (4).
The identification of new tumor antigens and the results from preliminary clinical trials are reasons for cautious optimism. Despite the recent strides in identification of tumor antigens and the technical advances in genetic immunotherapy, our understanding of the host's failure to respond to these antigens is in its infancy. The pathway to clinical application of these newly defined antigens will require studies that contribute to a more complete picture of the complex tumor-host interactions that foster progressive tumor growth in thoracic malignancies.
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Footnotes |
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Address correspondence to: Steven M. Dubinett, M.D., Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, 37-131 Center for Health Sciences, 10833 LeConte Avenue, Los Angeles, CA 90095-1690. E-mail: sdubinet{at}ucla.edu
(Received in original form March 17, 2000).
Abbreviations: antigens, Ags; antigen presenting cell(s), APC; complementary DNA, cDNA; cytotoxic T lymphocyte(s), CTL; dendritic cells, DC; major histocompatibility complex, MHC; malignant mesothelioma, MM; prostaglandin E2, PGE2; serologic analysis of recombinant cDNA expression libraries, SEREX.| |
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