TMIC-75. ICAM-1 PROMOTES AN IMMUNOSUPPRESSIVE LANDSCAPE IN GLIOBLASTOMAS BY REGULATING THE PHENOTYPIC POLARIZATION STATE OF TUMOR ASSOCIATED MACROPHAGES

Abstract Glioblastoma (GBM) is a fatal adult CNS tumor, with a median overall survival of 12-15 months. Intercellular adhesion molecule 1 (ICAM-1) is a cell adhesion molecule whose expression is significantly greater in the mesenchymal transcriptional subtype of GBMs, whereby it is prognostic. We have previously shown that when ICAM-1 is knocked out in the tumor microenvironment (TME) of immune-competent GBM-bearing mice, these mice showed prolonged overall survival and reduced tumor volume. It is yet to be determined how ICAM-1 expression affects infiltration and functional polarization of tumor-associated macrophages (TAMs) and other immune cells in GBM, and if we can suppress the infiltration of M2-like TAMs into the TME by inhibiting ICAM-1. We used a mouse glioma model with and without knockout (KO) of the ICAM-1 gene and intracranially injected GL261 cells. ICAM-1 KO mice survived longer and had reduced tumor volume relative to wildtype, with survival and volume differences being rescued upon ICAM-1 bone marrow reconstitution. Upon endpoint, we performed cytometry by time-of-flight, and found that ICAM-1 KO tumors harbored a reduction in helper T cells, Tregs, and cytotoxic T cells, but an increased proportion in double-negative T cells relative to ICAM-1 WT tumors. ICAM-1 KO tumors also demonstrated an increased proportion of M1-like TAMs relative to M2-like. These results were validated upon administration of ISIS-3082 to tumor models, an antisense oligonucleotide for which a human-specific form has been fast-track approved for other diseases, that targets ICAM-1 transiently in peripheral immune cells prior to TME infiltration. These findings suggest that ICAM-1 expression influences immune cell infiltration, potentially modulates the functional state of TAMs towards a M1-like state, and that ICAM-1 may be targeted in TAMs to ‘reeducate’ them before entering the TME. This may be translated into clinical practice and combined with standards-of-care to render GBMs more sensitive to treatment.