Glioblastoma (GBM) is a highly aggressive and heterogeneous tumor, with a strong immunosuppressive tumor microenvironment (TME), in which tumor-associated macrophages (TAM) play a crucial role. This immunosuppressive phenotype is detrimental to the efficacy of chimeric antigen receptor (CAR) T cell therapy. We believe that oncolytic adenoviruses can overcome some of the mechanisms involved in TME immunosuppression. Here, we investigate the capacity of the oncolytic adenovirus ICO15K to reprogram the GBM TME, with a special focus on promoting the transition from a pro-tumoral M2 to a pro-inflammatory M1 TAM phenotype.
ICO15K was previously engineered to specifically infect and replicate in cancer cells. We used patient-derived GBM and mouse GBM cell lines and assessed their susceptibility to ICO15K in vitro. To study ICO15K-induced pro-inflammatory TAM phenotype both in human and mouse models in vitro, monocytes-derived macrophages or bone marrow-derived macrophages, respectively, were treated, and their gene profile was characterized by qRT-PCR. In vivo, immunocompetent mice bearing the SB28 mouse GBM cell line or the SB28-hCAR line modified to express the human coxsackie and adenovirus receptor (hCAR) for adenovirus entry were treated with PBS or ICO15K and the immune landscape of tumors was characterized.
We show that ICO15K is able to infect and exert a significant cytotoxicity effect in a panel of patient-derived cell lines, as well as in mouse SB28 and GL261 cell lines. In addition, both human and mouse M2 macrophages showed an ICO15K-induced transition towards an M1-like pro-inflammatory phenotype in vitro. In vivo, ICO15K-treated mice showed significant increased T cell infiltration and increased pro-inflammatory TME phenotype compared to non-treated mice.
Altogether, we present preliminary data of ICO15K-mediated TME modulation that could help to improve CAR T cell therapy. Further preclinical development of this strategy is needed to better understand its therapeutic impact for the improvement of GBM patient outcomes.
The authors.
ISREC.
All authors have declared no conflicts of interest.