Manipulation of the p53 pathway as a novel target for cancer immunotherapy


AU researchers have identified a novel population of immunogenic dendritic cells that arise from rapid transdifferentiation of immature myeloid-derived suppressor ceils (MOSCs) in tumors. We have discovered that this DC trans-differentiation step is driven by p53 expressed by the host (not the tumor). Mice with a deletion of p53 in host cells lose exactly this Ly6c+CD103+ DC population (and no others), and they become selectively unable to respond to all forms of anti-tumor immunotherapy that we have tested. Conversely (and with major implications for clinical immunotherapy) if we artificially activate the p53 pathway by systemically administering a known MDM2-antagonist drug such as nutlin-3a, then this markedly enhances and prolongs the response to multiple different forms of immunotherapy, including immunogenic chemotherapy, checkpoint blockade, etc. This enhancement occurs because pharmacologically inducing the p53 pathway increases and sustains the differentiation of the key Ly6c+ CD103+ immunogenic DC population in the tumor.

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Carl Clark
Director Technology Transfer
Augusta University
David Munn
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