TABLE 5.

Mechanisms of immunotherapy resistance in glioblastoma.

Category of resistance	Example of resistance	References
Primary	CNS immune privilege: 1. BBB 2. CNS lymphatics 3. Resident microglia	(Carson et al., 2006)
	Intrinsic tumor heterogeneity: 1. Classical subtypes 2. Non-classical hybrid cellular states	(Patel et al., 2014)
	Immunosuppressive tumor microenvironment: 1. T cell dysfunction & exhaustion 2. Monocyte/macrophage populations	(Woroniecka et al., 2018) (Marvel and Gabrilovich, 2015)
Secondary	SOC-induced changes: 1. Lymphopenia secondary to TMZ 2. Immunosuppressive cell populations upregulated secondary to dexamethasone	(Gustafson et al., 2010) (Karachi et al., 2018)
	Immunotherapeutic pressure: 1. Expression of alternative checkpoints (TIM3) 2. Epigenetic changes secondary to chronic IFN-γ 3. Loss of tumor antigen expression	(Koyama et al., 2016) (Benci et al., 2016)