Immu-05. Late Effects of Intracranial Radiation Induces Resistance to Immune Checkpoint Blockade Therapy That Is Partially Reversible With Csf-1r Inhibition
Year: 2018
Type: conference-abstract
Abstract: Primary and metastatic CNS malignancies remain incurable despite aggressive therapy with surgery and radiation. Immunotherapy has shown promise in many solid and hematologic malignancies, however, results have been disappointing in recurrent primary CNS tumors. Additionally, while upfront immune checkpoint blockade therapy (ICB) has shown equal efficacy intracranially and extracranially, these responses are abrogated in previously irradiated brain lesions. Together, we hypothesize that radiation modulates the brain microenvironment to permit tumor growth and suppress anti-tumor immunity. As such, we developed a mouse model whereby orthotopic transplantation of murine gliomas into previously irradiated normal brain results in a more aggressive tumor phenotype. Moreover, the ICB-sensitive glioma cell line, GL261, is resistant to ICB therapy when implanted into a previously irradiated brain microenvironment. Immunophenotyping revealed a decreased ratio of CD8:CD4 T cells within tumor-infiltrating lymphocytes isolated from previously irradiated mice though the relative frequency of neoantigen-specific CD8 T cells was slightly increased and no difference in PD-1 expression was observed. Alternatively, the frequency of microglia and tumor-infiltrating CD11b+ Gr-1+ myeloid-derived suppressor cells (MDSC) was increased following irradiation suggesting a potential role for these myeloid cells in the immunosuppressive effects noted. Consistently, the administration of a CSF-1R inhibitor, which has been shown to reduce the number of microglia and block MDSCs, partially resensitizes GL261 cells to ICB therapy. In summary, we have developed a model that recapitulates the late effects of radiation on immunotherapy-resistance in CNS tumors. Preliminary results suggest that these late radiation effects are mediated through an increased myeloid population, and that inhibition of these cell subsets via the CSF-1R pathway can partially restore efficacy of ICB therapy. Furthermore, this model may provide further insight into additional therapeutic strategies that can be used to overcome these mechanisms of resistance induced by radiation therapy in the CNS.
Source: Neuro-Oncology
Institution: Washington University in St. Louis
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2900296361