Combined Immunotherapy Against Cancer: Limited Efficacy of Transcutaneous Immunization and Low-dose Cyclophosphamide

摘要

Transcutaneous immunization (TCI) is a novel vaccination strategy with a promising potential for combating tumors or persistent infectious diseases. However, imiquimod-based TCI, we have previously developed, shows only limited effectiveness in terms of tumor protection, partly due to suppression by regulatory T (Treg) cells. To improve the vaccination potency we combined TCI with the cytotoxic drug cyclophosphamide (Cy) that is used for the treatment of tumors and described to mediate inactivation of Treg cells at low doses. Cy only slightly reduced Treg cell numbers in a concentration dependent manner under the chosen conditions, but also enhanced DC activation. Therefore, we used Cy-TCI in a therapeutic tumor assay where E.G7 lymphomas were subcutaneously transplanted and allowed to grow until palpable before the treatments started. Interestingly, the rates of tumor protection in TCI or Cy-TCI treated groups were identical. Towards the underlying mechanisms of the failure of Cy-TCI to provide enhanced tumor protection, we observed increased numbers of monocytic and granulocytic immature myeloid cells after Cy-TCI, partly suppressing TCI-induced immune responses. Taken together, we suggest that Cy-TCI induces inhibitory mechanisms counterregulating TCI enhancing effects, therefore suppressing vaccination-induced immune responses.