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)