Time Dependency of Anti-PDL1 Checkpoint Blockade Efficacy Against PDL1-Negative Medulloblastoma
Mentor: Dr. Alex Huang
Emerging data support a critical role for PD-L1/PD-1 signaling in tumor immunity, with dramatic responses of some therapy-refractory cancers to checkpoint blockade. However, a significant number of patients do not benefit, and additional mechanistic insights are needed to improve current therapies and to provide strong scientific basis for combination trial designs. Recently, our laboratory reported that Cyclin-dependent Kinase 5 (Cdk5) has a critical role in regulating tumor Programmed Death-Ligand 1 (PD-L1) in response to interferon-gamma (IFNγ) in a murine medulloblastoma (MB) model. Cdk5def MB enhanced tumor microenvironment (TME) IFNγ contents and increased PD-L1 expression on lymphoid and myeloid cells. Over the past few months, we have generated data showing a surprising time-dependent efficacy of anti-PD-L1 blockade in PD-L1neg MB. 5x104 PD-L1def MB resulted in a 50% tumor incidence as compared to 100% tumor incidence with wild type MB. Surprisingly, weekly administration of anti-PD-L1 antibody in mice bearing PD-L1def MB starting at 7 days following tumor inoculation resulted in 100% tumor rejection, while injection of antibody treatment starting on day 0 resulted in only 30-50% tumor-free incidence. Our data support the hypothesis that: 1) the absence of tumor PD-L1 does not preclude the utility of checkpoint blockade; and 2) PD-L1/PD1 interaction during early anti-tumor immune priming is beneficial, as day 0 blockade of PD-L1 resulted in diminished tumor rejection rates in comparison to same blockade administered starting on day 7. For the current POST proposal, the POST fellow will assess a functional change in the capacity of myeloid CD11c+ DC in activating naïve T cells in the presence and absence of PD-L1 blockade by performing a series of in vitro T cell proliferation and functional assays using a model tumor antigen, Ovalbumin. The POST Fellow will also characterize changes in immune cellular landscape within PD-L1neg TME undergoing differentially timed anti-PD-L1 blockade. We aim to provide scientific rationale for a time-dependent application of checkpoint blockade in PD-L1lo tumors for future design of tumor vaccine and immunotherapy trials in pediatric cancer.
