Novel murine glioblastoma models that reflect the immunotherapy resistance profile of a human disease

Background The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We, therefore, developed murine glioblastoma stem cell lines derived from Nestin-CreER(T2) Qk(L/L); Trp53(L/L); Pten(L/L) (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and their underlying mechanisms. Methods The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on the responsiveness of each tumor was measured through whole exome sequencing. The immune microenvironments of sensitive (QPP7) versus resistant (QPP8) lines were compared in the brain using flow cytometry. Drivers of flank sensitivity versus brain resistance were also measured for QPP8. Results QPP lines are syngeneic to C57BL/6J mice and demonstrate varied sensitivities to T cell immune checkpoint blockade ranging from curative responses to complete resistance. Infiltrating tumor immune analysis of QPP8 reveals improved T cell fitness and augmented effector-to-suppressor ratios when implanted subcutaneously (sensitive), which are absent on implantation in the brain (resistant). Upregulation of PD-L1 across the myeloid stroma acts to establish this state of immune privilege in the brain. In contrast, QPP7 responds to checkpoint immunotherapy even in the brain likely resulting from its elevated neoantigen burden. Conclusions These syngeneic QPP models of glioblastoma demonstrate clinically relevant profiles of immunotherapeutic sensitivity and potential utility for both mechanistic discovery and evaluation of immune therapies.

Automated summary

This study developed murine glioblastoma stem cell lines with clinically relevant genetic mutations and evaluated their immune sensitivities in immunocompetent hosts. The results showed that different cell lines have varying sensitivities to T cell immune checkpoint blockade, and there are differences between the brain and flank. Immunological analysis revealed that upregulation of PD-L1 on myeloid stroma establishes immune privilege in the brain. However, QPP7 cell line showed response to immunotherapy even in the brain due to its elevated neoantigen burden. These mouse models can be used for mechanistic discovery and evaluation of immune therapies.