Targeting Syk to enhance anti-tumor immune responses in neuroblastoma

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PROJECT SUMMARY/ABSTRACT: There is critical need to develop novel therapies for neuroblastoma (NB). NB is the most common extracranial pediatric cancer and even after aggressive multimodal treatments, high-risk patients succumb to progressive disease. One of the reasons underlying failure of these therapies in NB is the highly immunosuppressive tumor microenvironment generated by tumor associated macrophages (TAMs) that inhibit both innate and adaptive immune responses. The long-term goal is to better understand the signaling mechanisms by which TAMs mediate tumor immunosuppression and inhibit anti-tumor immune responses in high-risk NB. The overall objectives in this particular application are 1) to determine the role of spleen tyrosine kinase (Syk) in macrophage (MΦ)-mediated immunosuppression in MYCN and non-MYCN amplified (MYCN-NA) NB tumors and 2) to test whether Syk inhibitors combined with immune checkpoint inhibitors or standard care of therapies can improve anti-tumor immune responses in NB. The central hypothesis motivating this research is that Syk in immunosuppressive TAMs inhibits T cell responses and promotes resistance to checkpoint inhibitors in mouse models of NB. This hypothesis has been formulated on the basis of evidences generated in our laboratory utilizing Syk inhibitors and Syk-/- murine models for immuno-oncology. The rationale for the proposed research is that understanding molecular mechanisms by which Syk promote immunosuppression in MYCN and non- MYCN amplified (MYCN-NA) tumors has the potential to identify an immunological signature which will predict responsiveness to Syk inhibitors in NB tumors driven by a Syk-MΦ-dependent immunosuppressive TME. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: in Aim 1, we will evaluate the effects of myeloid Syk deficiency on NB tumor microenvironment and infiltrating immune populations. In Aim 2, we will investigate molecular mechanisms by which Syk regulate immunosuppressive MΦ polarization in MYCN and MYCN-NA NB tumors. In Aim 3, we will determine whether Syk inhibitors in combination with checkpoint blockade or current therapies can augment anti-tumor immune responses in NB. The significance of our proposal lies in our capacity to develop novel combinatorial therapy of Syk inhibitors with immunotherapy or standard of care therapies that is more effective than current therapies in NB.