Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Immune therapies such as immune checkpoint inhibitors have had a profound impact on cancer patient survival and quality of life. However, clinical data is now emerging that immune checkpoint inhibitors may only benefit subsets of patients that have high mutational loads, T cell infiltration, PD-L1 expression, defects in DNA mismatch repair, and microsatellite instability. Comprehensive profiling reveals that these favorable predisposing factors are not common within glioblastoma. Glioblastoma represents a prototypical example of an “immunologically cold” tumor. Nonetheless, there are isolated areas in which CD8 T cells are present in the glioblastoma microenvironment but we do not know understand what induces these immune hotspots of reactivity. This proposal will determine what is triggering focal adaptive immune responses. Until now, most studies have focused on immune responses within the tumor. Based on a series of observation of inflammatory responses at the tumor-infiltrative brain edge, we are now focusing on a more detailed evaluation of anti-tumor immune responses at this interface, which likely differs from those in the tumor mass itself. This discrepancy is probably misinforming the scientific community regarding biomarkers of potential response and missing key pathways and mechanisms that are important for antitumor immune surveillance and eradication. In the case of cancer in the CNS, the adjacent brain is “damaged” or stressed, thereby upregulating the expression of immune chemokines. Notably, we are taking this observation several steps further and creating topographical immune atlases of the tumor-CNS interface, in order to more fully understand what controls localized immunological reactivity. Many of the observations that we will potentially make regarding enrichment of immune reactivity within the tumor landscape are likely to hold true for other organ sites, but we also suspect that there will be truly unique CNS-specific observations. Furthermore, in order for us to prioritize available immune therapeutic strategies, this proposal will also be profiling both the innate and adaptive arm of the immune system for common operational mechanisms of immune suppression. To trigger a flood of T cell infiltration into otherwise “cold” tumors through pro-inflammatory activation of suppressive tumor stroma, we have created a novel STING (stimulator of interferon genes) agonist. STING is a widely expressed sensor of cellular stress, specifically the presence of DNA in the cytoplasm that bridges the innate and adaptive immune systems both by triggering interferon release and through cis-activation of myeloid cells. Distinct from most other innate immune agonists, STING activation can re-educate tumor supportive M2 macrophages toward a pro-inflammatory M1 phenotype and can reverse the suppressive phenotype of myeloid-derived suppressor cells. Preclinical data from our laboratory demonstrates that STING agonists have therapeutic activity in established murine models of glioma. Ultimately, we plan to advance STING agonists into clinical trials that can be monitored for T cell infiltration using our unique radiomic textural MRI assessments. PHS 398 (Rev. 06/09)
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