Vaccine Therapy and Immunotherapy for Cancer: Gene-expression Profiling

T-cell Transcriptional Profile after Immunization

In longitudinal studies conducted in transgenic mouse models, Kaech SM et al. analyzed the transcriptional profile of CD8⁺ T cells following acute exposure to antigen and characterized distinct phenotypes at different time points from antigen exposure.^[24,25] These studies suggested a continuous spectrum of CD8⁺ T-cell development from naive to effector to memory T cells, of which the classical effector and memory phenotypes represent the extremes. During the first week, a rapid expansion of CD8⁺ T cells is observed, in which CD8⁺ T cells are cytotoxic ex vivo and display a genetic profile rich in effector/activated T-cell features, including granzyme A and B, perforin and Fas ligand. In the following contraction phase, a memory phenotype ensues, characterized by ability to produce IFN-γ in response to cognate stimulation but lack of lytic activity and loose the expression of genes associated with T-cell effector function. This model fits well with immunization-induced T cells due to the dynamics of cancer vaccine therapy, which exposes the organism to specific antigenic stimulation in time followed by a rest period.^[26,27] We studied the functional status of circulating CD8⁺ vaccine-induced T cells in metastatic melanoma patients undergoing vaccination using a HLA class I-restricted, modified peptide called gp100 (209-2M), derived from gp100 (a melanoma TA involved in the synthesis of melanin). Although such lymphocytes retain an effector phenotype according to canonical markers (CD27⁻, CCR7⁻ and CD45RA^high) and can respond with IFN-γ secretion to cognate stimulation, they do not express perforin and cannot exert effector functions.^[28] In a following microarray study, we better characterized a 'quiescent' phenotype of immunization-induced T cells lacking direct ex vivo cytotoxic and proliferative potential.^[27] Transcriptional profiling of quiescent circulating tumor-specific CD8⁺ T cells demonstrated that they lack expression of genes associated with T-cell activation, proliferation and effector function (e.g., CCR5, CXCR3, perforin and granzyme A). This quiescent status may explain the observed lack of correlation between the presence of circulating immunization-induced lymphocytes and tumor regression. In fact, we had previously shown that circulating, vaccine-induced T cells can reach tumor deposits and interact with tumor cells producing IFN-γ without leading to tumor destruction.^[29]

However, the lack of a proliferative and cytotoxic response of TA-specific T cells can be recovered by in vitro antigen recall and IL-2, suggesting that a complete effector phenotype might be reinstated in vivo to fulfill the potential of anticancer vaccine protocols if similar conditions could be provided.^[14,27] It is likely that, at the tumor site, immunization-induced T cells are exposed to antigen recall but they are probably not exposed to the costimulatory drive modeled by the addition of IL-2 in in vitro conditions.^[30] Accordingly, while vaccination alone only rarely induces tumor regression,^[31] the combined administration of immune modulators such as IL-2 appears to enhance its clinical effectiveness, suggesting that other factors are required in vivo for the full activation of tumor-specific T cells. In a pivotal study involving metastatic melanoma patients, only the association of gp100 (209-2M) and IL-2 obtained a considerable rate of tumor response (42%), whereas the administration of vaccine alone did not produce any clinical benefit.^[32] The results of three independent Phase II trials attributed the observed favorable outcome to the IL-2 rather than to the vaccine component.^[33] However, a recent randomized multicenter clinical trial has finally confirmed that the combination of high-dose IL-2 administration with active specific immunization yields better results than either treatment alone.^[34]

Understanding the effect of costimulation molecules, such as IL-2, in the tumor microenvironment might be the key to successful implementation of TA-specific anticancer therapies.^[12–14,35]

Cite this: Gene-expression Profiling in Vaccine Therapy and Immunotherapy for Cancer - Medscape - Jun 01, 2010.

Sidebar

Key Issues

In the field of anticancer vaccine therapy, the immunologic end point (evaluation of tumor antigen-specific T cells) is not a surrogate of the clinical end point (response rate or overall survival). Clinical trials have definitely shown that highly specific T-cell responses can be generated. Nevertheless, clinical results are disappointing. These data indicate that immune-mediated tumor rejection requires more than simple T-cell/target interaction.
The biological explanations for the dichotomy between immunological and clinical end points remain elusive.
Tumor immunology is a compound field that merges the intricacy of human immunology with the complex biology of cancer. Experimental models created to bypass such complexity by inbreeding animals and standardizing cancers miss such basic essence and studies in humans are needed. Understanding the phenomena of the tumor immune response cannot avoid a high-throughput discovery-driven approach applied to the study of the microenvironment at appropriate time points.
Through this approach, the following concepts emerge:
- Lesions likely to respond to therapy are preconditioned by an immunologically active microenvironment
- Tumor regression is associated with switch from chronic to acute inflammation
- IL-2 does not promote migration of cytotoxic T cells to the tumor microenvironment nor their activation or proliferation but rather induces a cytokine storm responsible for the release of a broad array of immune stimulatory cytokines by circulating immune cells
- Beyond the direct cytotoxic mechanism, mediated by interaction of specific T cells with their target cells, T cells could be considered a vehicle to deliver general proinflammatory signals in a selective manner
- The molecular mechanisms activated during immune-mediated tissue destruction are shared by other, apparently unrelated, immune-mediated tissue destruction process (e.g., allograft rejection, viral clearance and graft-versus-host disease)
We proposed a convergent molecular mechanism associated with immune-mediated tissue destruction that we named 'immunological constant of rejection'. This constant include the coordinate activation of the interferon-stimulated genes and the immune-effector functions.
We summarized the functional units of the immunological constant of rejection:
- STAT-1/IRF-1/T-bet/IFN-γ, IL-15 pathway
- Granzyme A/B, TIA-1 pathway
- CXCR3 ligand chemokine pathway
- CCR5 ligand chemokine pathway
Identifying the clinical mechanisms that lead to this final common pathway in individual tumors may define a better rationale for targeted therapies that may take advantage of each individual cancer's biology.

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