Blocking CD13 in combination with a toll like receptor agonist increases the efficacy of cancer vaccine adjuvants
Veneta Qendro, Mallika Ghosh, Linda H. Shapiro*
University of Connecticut Medical School
Vaccines have been extraordinarily successful in the fight against human disease by exploiting the immune system to recognize and eliminate abnormal cells or pathogenic organisms. Similarly, recent advances in cancer biology have led to the development of two FDA approved anti-cancer vaccines for cervical and prostate cancer. Despite the progress that these vaccines represent, the components of these vaccines are often poorly immunogenic. Therefore, developing effective cancer vaccine adjuvants has become a major research focus. MPLA (monophosphorylated lipid A) is a synthetic analog of LPS that vigorously activates the adaptive immune response without triggering the inherent LPS inflammatory properties. Using the TRIF-biased, less inflammatory signal transduction pathway, MPLA leads to increased antigen-targeted cytotoxic T cell responses. As such, MPLA has recently been approved by FDA as a component of the HPV-driven (Human Papilloma Virus) cervical cancer vaccine Cervarix. CD13 is a multifunctional cell surface peptidase, constitutively expressed on all lineages of myeloid cells that regulates receptor mediated endocytosis and endosomal trafficking. We have previously shown that lack of CD13 increases tumor antigen uptake and presentation, resulting in enhanced activation of tumor-specific cytotoxic T cells. Mechanistically, we have found that lack or blocking of CD13 increases TLR4 endocytosis towards the same MPLA-triggered, less inflammatory endocytic pathway, resulting in reduced deleterious inflammatory responses and enhanced T cell killing. Taken together, these facts lead to the intriguing possibility that blocking CD13 in conjunction with MPLA administration may prove to be a superior adjuvant to MPLA alone. Therefore, we hypothesize that CD13 blocking monoclonal antibodies in combination with MPLA will act as dual-action adjuvants and promote TLR4 endocytosis, thus amplification of vaccine efficacy and specificity.
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