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Neoplastic growths represent a unique challenge for the host immune system. As they are indeed derived from self, many of the same mechanisms operating to prevent autoimmunity also provide an umbrella beneath which malignant cells are free to proliferate.1 Central among these immune regulatory boundaries are an influential subset of lymphocytes known as T regs. Hypothesized to exist decades ago, yet eluding definitive characterization until relatively recently, T regs have been demonstrated to play a crucial role in the proper functioning of the immune system as a whole. They may also, however, represent one of the primary obstacles to successful anti-tumor immunotherapies. The T regulatory class of lymphocytes, can itself be subdivided into several distinct populations, each possessing the ability to suppress the immune response through a variety of often overlapping methods. Some of these subgroups are inducible through humoral cues present within the local microenvironment, as well as via direct cell to cell interactions. Others are assigned more permanent roles during thymic maturation. To date, the surface marker most frequently associated with thymic derived T regs, is the high-affinity chain of the IL-2 receptor, CD25. Multiple experiments have confirmed that depletion of lymphocytes displaying this molecule leads to an increase in immune mediated tumor rejection.2, 3, 4 However, CD25 is not an absolute marker for regulatory activity in vivo. It is also found on the surface of activated effector T cells. In addition, lymphocytes capable of regulatory activity, yet lacking CD25, have been isolated.5 Thus, lympho-depletion of CD25+ cells, although offering proof of principle, may also be counterproductive owing to the elimination of potentially tumor reactive effector cells. The forkhead family transcriptional regulator FOXP3 appears to be a more reliable marker of regulatory potential. It does not, however, define the entire regulatory pool, as some non-FOXP3 expressing suppressor cells have been characterized. However, FOXP3-dependent T regs seem to play a major role in establishing self-tolerance. This is most clearly demonstrated by the fatal human autoimmune disorder IPEX (immunodysregulation, polyendicronopathy, enteropathy, X-linked), which is caused by mutations in the FOXP3 gene. Besides its integral role in the thymic development and function of mature T regs, FOXP3 has also been found, to directly suppress the transcription of cytokines responsible for initiating and perpetuating an effective immune response, in cells targeted for regulatory suppression.6 This normally beneficial physiological repression of potentially self-reactive lymphocytes may have lethal consequences in the pathological context of malignancy. Owing to the intracellular localization of FOXP3, however, it is not readily accessible using traditional methods of in vivo targeting. The recent emergence of RNAi offers a novel opportunity for post-transcriptional suppression of foxp3 production in vivo. Several traits of RNAi technologies, in their current state, bode well for the potential applicability of this tool toward in vivo suppression of T reg activity. First, the transient nature of knockdowns mediated by pre-synthesized small interfering RNAs, would be advantageous in a clinical setting, allowing for the suppression of regulatory cells, only as long as therapeutically necessary. Second, though advances in systemic delivery are emerging at a rapid pace, effective local transfection in vivo is still much more readily achievable. Experimental evidence indicates that FOXP3-dependent T regs exert much of their suppressive effects intratumorally and within the draining lymph nodes.1, 4 Quantitative measurements of T reg presence within tumor ascites has revealed a negative correlation between the number of these cells present and patient survival in ovarian carcinoma.1 Thus local transfection, focused upon a single tumor and its draining lymph nodes, might serve as an apt starting point for testing the impact of RNAi mediated FOXP3 knockdown upon tumor immunity. The greatest advantage of this technique lies in its ability to repress regulatory pathways without depleting effector lymphocytes. Recent evidence indicates that inhibiting cell-mediated immune tolerance can work synergistically with concurrent exposure to relevant tumor antigens.7, 8 This illustrates the fact that regulatory cells can be seen as shielding neoplasms, through dominant tolerance, from immunotherapies, which seek to activate tumor reactive effector lymphocytes. FOXP3 expressing regulatory cells are also believed to interact with dendritic cells to promote suppression of the immune response. As mentioned earlier, not all regulatory cells express FOXP3. The existence of a peripherally induced subset, of IL-10 secreting, CD-8+ lymphocytes capable of regulatory activity, independent of FOXP3, has recently been observed. It has been demonstrated in vitro that these cells can be induced via the actions of plasmacytoid dendritic cells.9 This was found to be possible even in the absence of CD-25+ regulatory cells. One might seek to avoid induction of these suppressors by specifically targeting vaccination attempts toward myeloid DCs. It is unknown at the present time what the comparative contribution in vivo each of these regulatory populations makes to self-tolerance as a whole. Knockdown of FOXP3 expression in T regs offers the possibility of shedding new light upon this question. There no doubt exist, multiple mechanisms via which the immune system creates the phenomena of immunodominant self-tolerance. To initiate an effective anti-neoplastic immune response, however, it seems likely that we need not target all or even a majority of these mechanisms. It would be desirable from a clinical perspective to shift the balance, only just so much as to break peripheral tolerance enough to permit active tumor immunity. It seems plausible that local RNAi-mediated knockdown of FOXP3-dependent T reg function might lower the bar of immune tolerance enough, as to allow presentation of introduced tumor associated antigens by APCs, and subsequent clonal proliferation of tumor-reactive lymphocytes. The possibility of initiating a systemic immune response hints that local suppression of T regs, in combination with relevant tumor associated antigen exposure, may in fact offer the prospect of impacting disseminated neoplasms. Such a reaction would need to attain sufficient momentum as to overcome the individual regulatory microenvironments surrounding each tumor mass, including FOXP3-negative IL-10-producing cells. It may be revealed, however, that FOXP3-dependent lymphocytes contribute, in a more general sense, to producing a systemic climate conducive toward immunosuppression, which can be substantially influenced via the selective targeting of this important protein in vivo.

Potential for stimulating host anti-tumor immune response via RNAi-mediated local FOXP3 knockdown