Mechanisms of immunotherapy resistance: lessons from glioblastoma


Glioblastoma (GBM) is the deadliest form of brain cancer, with a median survival of less than 2 years despite surgical resection, radiation, and chemotherapy. GBM’s rapid progression, resistance to therapy, and inexorable recurrence have been attributed to several factors, including its rapid growth rate, its molecular heterogeneity, its propensity to infiltrate vital brain structures, the regenerative capacity of treatment-resistant cancer stem cells, and challenges in achieving high concentrations of chemotherapeutic agents in the central nervous system. Escape from immunosurveillance is increasingly recognized as a landmark event in cancer biology. Translation of this framework to clinical oncology has positioned immunotherapy as a pillar of cancer treatment. Amid the bourgeoning successes of cancer immunotherapy, GBM has emerged as a model of resistance to immunotherapy. Here we review the mechanisms of immunotherapy resistance in GBM and discuss how insights into GBM–immune system interactions might inform the next generation of immunotherapeutics for GBM and other resistant pathologies.

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Fig. 1
Fig. 2: Mechanisms of systemic immunosuppression in GBM.
Fig. 3: Selected therapeutic approaches for GBM and their immunological targets.
Fig. 4: Cycle of immunotherapy resistance involving intrinsic, adaptive, and acquired mechanisms.


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Correspondence to Michael Lim.

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M.L. receives research support from Arbor, Aegenus, Altor, Accuray, and DNAtrix and serves as a consultant for Tocagen, SQZ Technologies, Bristol–Myers Squibb, Stryker, and Baxter.

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