Immune Checkpoint Inhibitors are Ineffective in Glioblastoma – Could LOX and OLFML3 be to blame?

Glioblastoma (GBM) is the most lethal form of primary brain cancer in adults. Scientists have been successful in categorizing GMB using genomic profiling and identifying the genetic alterations in core signaling pathways that drive certain GBMs. However, the promise of targeted therapies using this information have failed thus far. Dr. Chen’s work suggests that one reason for this failure may be the heterogeneity of the tumor microenvironment; tumor-associate macrophages and microglia (TAMs) can account for as much as half of the whole GBM tumor mass. Dr. Chen has identified two immuno-reactive cytokines (LOX and OLFML3) which seem to be particularly linked to the infiltration of TAMs in PTEN-deficient GBM. (PTEN is a type of protein that controls cell division and acts as a tumor suppressor.)  Building on this finding, Dr. Chen proposes to target both macrophages and microglia in PTEN-deficient GBM and the roles that the chemokines LOX and OLFML3 might play. In PTEN-deficient glioblastoma, TAMs are immunosuppressive cells and preliminary data shows that by blocking macrophage infiltration, LOX inhibition activates anti-tumor immune response and synergizes with immune checkpoint inhibitors (e.g., anti-PD1 therapy).

By targeting macrophages and microglia by inhibiting LOX and OLFML3 and combining the process with immune checkpoint inhibitors, Dr. Chen hopes to develop new potential therapies. Through his CRF Young Investigator project, Dr. Chen plans to learn about whether and how OLFML3 is up-regulated by LOX inhibition and to potentially develop novel therapeutic strategies against this interplay by inhibition of both LOX and OLFML3. By employing integrated strategies combining gain- and loss-of-function approaches, using in vitro and in vivo systems, as well as proteomic and transcriptomic analysis, Dr. Chen hopes to uncover novel mechanisms underlying TAMs in GBM progression and immunosuppression and to provide new immunotherapeutic strategies for PTEN-deficient GBM.