Upregulated expression of MHC I and II bearing leukemic peptides, costimulatory molecules, as well as

Upregulated expression of MHC I and II bearing leukemic peptides, costimulatory molecules, as well as interferon alpha production, in a milieu that would not only rescue the CML-specific T cells from anergy, but also induce their proliferation, expansion, and acquisition of cytotoxic/ leukemia inhibitory function. Several questions arise… First, will the DC that are activated by AldaraTM treatment actually express BCR-ABL peptides? Some believe that plasmacytoid DC are only derived from lymphoid lineage and thus will be BCR-ABL negative. To this question we respond by stating the main anti-CML effect of the AldaraTM treatment will not be through the direct activation of the plasmacytoid DC, but through the indirect activation of the myeloid derived DC that PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28380356 occurs as a result of the immune stimulation. For example it was demonstrated that not only does AldaraTM treatment potently induce maturation of myeloid DC through indirect effects [82], but also that local treatment induces migration of such cells to spleen, where in conjunction with NKT cell activation results in induction of systemic immune modulation capable of promoting antigen-specific immunity in a melanoma model [83]. Therefore we anticipate that the activation of myeloid DC will induce an increased presentation of anti-leukemic T effector cells. Additionally, the known effects of AldaraTM in activating NK cellfunction are also postulated to contribute to anti-leukemic effect [84]. Second, will the CML-specific T cells not be anergized in vivo, such that even if the presentation of BCR-ABL peptides does occur, the T cells will not be able to mount a productive anti-leukemic response? Although it was previously stated that Sodium lasalocidMedChemExpress Sodium lasalocid anergy to CML-specific T cells occurs in CML patients, this anergy seems reversible either by addition of cytokines or antigen-specific vaccination. The recent reports of hematologic and cytogenetic remissions induced by immunization with BCR-ABL peptides support this notion. Interestingly it was observed that higher antigen-specific responses occur in patients that are concurrently receiving interferon alpha [85-87]. These observations suggest that T cell clones specific for CML may indeed by reactivated in vivo, in a similar manner to how ex vivo IL-2 treatment of T cells induces escape from anergy [88]. Indeed imiquimod has been demonstrated to increase expression of CD80 and CD86, which are involved in escape from anergy [89,90], as well as upregulate production of IL-12 [91] which inhibits IL-10 generation [92], known to be responsible for maintaining the anergic state [93]. Along these lines, it is reported that upregulation of costimulatory molecules on circulating tumor cells in CLL patients following topical administration of imiquimod occurs, thus supporting the possibility that local administration of this agent may have systemic effects [94]. Third, what about CML specific antigens that are not expressed endogenously in DC of CML patients? Specifically, antigens such as telomerase [95], PR1 [29], PASD1 [96], CML28 and 66 [97] have not been identified in CML derived DC although immune responses to these have been observed in patients. To this we first answer that healthy, non-leukemic derived DC should theoretically engulf and present antigens derived from leukemic cells due to their “immunological sentinel” role. Therefore the activation of DC will allow, to some extent, presentation of leukemic antigens that are non-endogenous to the DC. Seco.