Dynamic Monitoring Of Anticancer Immune Responses

Although genetic background may be responsible for immune responsiveness, it is also possible that the unstable nature of cancer cell phenotypes can strongly influence the susceptibility of cancerous lesions to immune attack. In fact very little is known about the algorithm that may determine the occurrence of immune-induced cancer regression in humans (56). The introduction of gene profiling arrays is particularly suited to circumstances when little is known about a biological event to conceive plausible hypotheses. This is clearly the case of immune-mediate cancer rejection. We tested whether global transcript analysis could segregate lesions likely to respond to immunotherapy by obtaining FNA from subcutaneous melanoma metastases prior to immunotherapy (49). This work was based on a previous observation suggesting that cutaneous melanomas can be segregated into two distinct taxonomies based on global transcript analysis (57). Such observation stimulated the question of whether two disease pathologically defined as melanomas had a different biology and consequently, perhaps, different predisposition to respond to immune therapy. However, the original observation was based on the analysis of cell lines or tissue preparations that has been collected a long time before and for which very little information about the clinical outcome of the patient from which they were obtained was available. By prospectively collecting clinical information on those lesions from which FNA samples had been obtained, it was possible to link directly their gene expression profile to their response to therapy. In addition, since FNA allows serial sampling, it was possible to monitor the changes in the transcriptional profile occurring with time and/or in response to therapy in individual lesions. The results of this study underlined the importance of introducing a temporal dimension to the study of cancer biology. By studying the transcriptional changes of individual lesions with time whether or not in relation to treatment it was possible to understand that the two melanoma subgroups did not represent two distinct disease taxonomies but rather two stages of the same disease rapidly evolving because of its intrinsic instability (12). Indeed, it appeared that the two subclasses of melanoma represented two different stages of differentiation with one displaying a transcriptional profile close to normal melanocytes and the second cluster including later samples with an undifferentiated phenotype characteristic of a more advanced stage of disease (49). Although categorization of melanomas failed to predict immune responsiveness, it was possible to identify more subtle predictors of immune responsiveness by separating lesions that regressed from those that did not in response to therapy. In fact, a supervised analysis of lesions according that did or did not respond to active-specific immunization combined with IL-2 administration identified several genes whose level of expression could predict of immune responsiveness. Analysis of functional annotations revealed that these genes were predominantly associated with immune function suggesting that analysis of tumor deposits before therapy is informative as it demonstrates that some tumors are pre-conditioned to respond perhaps because their tumor microenvironment is more immunologically active before treatment administration (49). Several genes associated of immune responsiveness were of particular interest. For instance, interferon-regulatory factor-2 (IRF-2) was found to be over-expressed in lesions predisposed to respond to therapy. Since this gene up regulation is often seen in chronic inflammation this finding suggests that tumors likely to respond are chronically inflamed before treatment and this chronic inflammatory process may be beneficial or favorable to the outcome of immune therapy. Obviously, the inflammatory process is not sufficient in itself to induce tumor rejection without therapy and it may be beneficial for tumor growth, but it may set the stage for a conversion to an acute inflammatory process by recruiting immune cells at the tumor site that can be, in turn activated, by exogenous immune stimulation (58). A paired analysis of FNA samples obtained before and during therapy underlined this possibility since lesions that underwent complete response over-expressed of IRF-1 during therapy. IRF-1 acts as a counterpart to IRF-2 and its expression is up regulated during the development of an acute inflammatory process (59). Interestingly, lesions that did not undergo regression did not demonstrate any significant changes in their transcriptional profile in response to therapy (49).

It remains unclear why some tumors may behave differently than others and why some are more likely to be triggered into an acute inflammatory process. Some have suggested that inflammation is beneficial and necessary for tumor growth (60;61). This observation is not contrasting with our observation that acute inflammation may be necessary to induce cancer regression. Moderate inflammation may be helpful for the promotion of angiogenesis or may act as a direct stimulus to tumor growth as many factors released during tissue remodeling and repair have stimulatory effects on tumor cell growth. Thus, growth factor produced by tumor cells for the selfish purpose of survival may mimic the normal response of the organism to injury that promotes repair. This beneficial biological process may at the same time act on immune cells as inflammation and repair collaborate in response to injury. In fact, several growth factors have chemo-attractant and regulatory properties on immune cells. These molecules can induce the migration of cell of the innate and adaptive immune system within the tumor microenvironment. Such cells are probably not capable by themselves to exert anti-cancer properties but could rapidly turn into powerful effector anti-cancer cells given appropriate stimulatory conditions that may be induced by treatment such as the systemic administration of IL-2 (50).

In an effort to identify what conditions are most likely to turn and indolent chronic inflammatory process within the tumor site into an acute auto-immune rejection of cancer we studies the mechanism of action of IL-2. This cytokine is a powerful anti-cancer agent that has not direct effects of cancer cells growth IL-2 seems to increase the chances that tumor lesions are conditioned toward a switch from chronic to acute inflammation. In fact, although clinical responses are relatively rare, their dramatic occurrence is characterized by a rapid disappearance of large tumor bulks and in some instances long term disease free survival (3).Thus, IL-2 is the best gauge we have presently to study the mechanism(s) responsible for immune responsiveness in humans.

The effects of IL-2 are, independently of their therapeutic effects, are of extreme biological interest and it is surprising how little it is spent trying to understand its mechanism(s) of action. Some have suggested that IL-2 acts by facilitating the passage of tumor-specific T cells from the circulation to the tumor site by increasing blood vessels permeability (11). In addition, IL-2 has been considered a growth factor or activator of CD8+ T cells (62). Others postulated that IL-2 may induce activation of intra-tumoral endothelial cells which may in turn promote migration of TA-specific T cells within tumors (63). In addition, IL-2 induces a secondary production of an extensive array of cytokines through stimulation of circulating mononuclear cells that could have broader immune/pro-inflammatory effects than those expected by the interaction of IL-2 with its receptor (50;64;65). In a recent study we compared the early changes in the transcriptional profile of circulating mononuclear cells with those occurring within the tumor microenvironment of melanoma metastases following systemic IL-2 administration (50). The results of this study surprisingly suggested that the immediate effect of systemic IL-2 administration on the tumor microenvironment is a transcriptional activation of genes predominantly associated with monocyte function while minimal effects were noted on migration, activation and proliferation of T cells. Thus, this study suggested that IL-2 induces inflammation at tumor site with three predominant secondary effects: activation of antigen-presenting monocytes, massive production of chemo attractants that may recruit other immune cells to the tumor (including MIG and PARC) and activation of cytotoxic mechanisms in monocytes (calgranulin, grancalcin) and natural killer cells (NKG5, NK4) that may in turn contribute to epitope spreading through killing of cancer cells, uptake of shed antigens and presentation to adaptive immune cells.

This information is important in view of some recent unpublished work suggesting that circulating immunization-induced, TA-specific T cells are in a "quiescent" status of activation that requires for full activation the combination of antigen recall (readily available at tumor site) with a second signal possibly provided by pro-inflammatory cytokines or co-stimulatory molecules induced by the effects of IL-2 on the tumor microenvironment (66). Thus, it is obvious that the relationship between T cell and tumor cells within the tumor microenvironment should be the focus of future research since the determinism of immune responsiveness will be locked and submerged by factors that modulate the function of T cells in their target organs.

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