ABSTRACT 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

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BEING VIEWED BY OTHERS CHALLENGES IN GLIOBLASTOMA IMMUNOTHERAPY: MECHANISMS OF RESISTANCE AND THERAPEUTIC APPROACHES TO OVERCOME THEM Article 04 June 2022 IMMUNOTHERAPY FOR GLIOBLASTOMA:

CURRENT STATE, CHALLENGES, AND FUTURE PERSPECTIVES Article Open access 15 October 2024 FROM SIGNALLING PATHWAYS TO TARGETED THERAPIES: UNRAVELLING GLIOBLASTOMA’S SECRETS AND HARNESSING TWO

DECADES OF PROGRESS Article Open access 20 October 2023 REFERENCES * Nachman, M. W. & Crowell, S. L. Estimate of the mutation rate per nucleotide in humans. _Genetics_ 156, 297–304

(2000). CAS  PubMed  PubMed Central  Google Scholar  * Vogelstein, B. et al. Genetic alterations during colorectal-tumor development. _N. Engl. J. Med._ 319, 525–532 (1988). CAS  PubMed 

Google Scholar  * Hastings, K. G. et al. Socioeconomic differences in the epidemiologic transition from heart disease to cancer as the leading cause of death in the United States, 2003 to

2015: an observational study. _Ann. Intern. Med._ 169, 836–844 (2018). PubMed  Google Scholar  * Ribatti, D. The concept of immune surveillance against tumors. The first theories.

_Oncotarget_ 8, 7175–7180 (2017). PubMed  Google Scholar  * Dunn, G. P., Old, L. J. & Schreiber, R. D. The three Es of cancer immunoediting. _Annu. Rev. Immunol._ 22, 329–360 (2004).

THIS REVIEW (REF. 5) DESCRIBES THE INTERACTIONS BETWEEN A TUMOR AND THE IMMUNE SYSTEM THAT GOVERN TUMOR PROGRESSION OR CLEARANCE. THIS FRAMEWORK IS IMPORTANT FOR UNDERSTANDING HOW TUMORS

RESPOND TO IMMUNOLOGICAL PRESSURE. CAS  PubMed  Google Scholar  * Gong, J., Chehrazi-Raffle, A., Reddi, S. & Salgia, R. Development of PD-1 and PD-L1 inhibitors as a form of cancer

immunotherapy: a comprehensive review of registration trials and future considerations. _J. Immunother. Cancer_ 6, 765–2 (2018). Google Scholar  * Rizvi, N. A. et al. Cancer immunology.

Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. _Science_ 348, 124–128 (2015). THIS (REF. 7) WAS A LANDMARK STUDY HIGHLIGHTING THE CONNECTION

BETWEEN A TUMOR’S MUTATIONAL LANDSCAPE AND RESPONSE TO IMMUNE-CHECKPOINT BLOCKADE. CAS  PubMed  PubMed Central  Google Scholar  * Le, D. T. et al. Mismatch repair deficiency predicts

response of solid tumors to PD-1 blockade. _Science_ 357, 409–413 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Topalian, S. L. et al. Safety, activity, and immune correlates of

anti-PD-1 antibody in cancer. _N. Engl. J. Med._ 366, 2443–2454 (2012). THIS STUDY (REF. 9) DEMONSTRATED THE CLINICAL ACTIVITY OF PD-1 BLOCKADE AND ESTABLISHED PD-L1 EXPRESSION ON TUMOR

CELLS AS A BIOMARKER OF RESPONSE. CAS  PubMed  PubMed Central  Google Scholar  * Gibney, G. T., Weiner, L. M. & Atkins, M. B. Predictive biomarkers for checkpoint inhibitor-based

immunotherapy. _Lancet Oncol._ 17, e542–e551 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Zhao, J. et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in

glioblastoma. _Nat. Med._ 25, 462–469 (2019). PubMed  PubMed Central  Google Scholar  * Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance

to cancer immunotherapy. _Cell_ 168, 707–723 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. _Nat. Rev.

Cancer_ 12, 252–264 (2012). CAS  PubMed  PubMed Central  Google Scholar  * Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. _Nat. Immunol._ 19,

108–119 (2018). CAS  PubMed  PubMed Central  Google Scholar  * Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. _Nat. Med._

22, 851–860 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Lim, M., Xia, Y., Bettegowda, C. & Weller, M. Current state of immunotherapy for glioblastoma. _Nat. Rev. Clin.

Oncol._ 15, 422–442 (2018). CAS  PubMed  Google Scholar  * Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. _N. Engl. J. Med._ 373, 23–34 (2015).

PubMed  PubMed Central  Google Scholar  * Weller, M. et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised,

double-blind, international phase 3 trial. _Lancet Oncol._ 18, 1373–1385 (2017). CAS  PubMed  Google Scholar  * Omuro, A. et al. Nivolumab with or without ipilimumab in patients with

recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. _Neuro-oncol._ 20, 674–686 (2018). CAS  PubMed  Google Scholar  * Gettinger, S. N. et al. Clinical features

and management of acquired resistance to PD-1 axis inhibitors in 26 patients with advanced non-small cell lung cancer. _J. Thorac. Oncol._ 13, 831–839 (2018). PubMed  PubMed Central  Google

Scholar  * Comiskey, M. C., Dallos, M. C. & Drake, C. G. Immunotherapy in prostate cancer: teaching an old dog new tricks. _Curr. Oncol. Rep._ 20, 75 (2018). PubMed  Google Scholar  *

Louis, D. N. et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. _Acta Neuropathol._ 131, 803–820 (2016). PubMed  Google Scholar  *

Ostrom, Q.T., Gittleman, H., Stetson, L., Virk, S.M. & Barnholtz-Sloan, J.S. in _Current Understanding and Treatment of Gliomas_ Vol. 163, pp. 1–14 (Springer International Publishing,

2014). * Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. _N. Engl. J. Med._ 352, 987–996 (2005). THIS TRIAL (REF. 24) ESTABLISHED THE CURRENT

STANDARD OF CARE FOR PATIENTS WITH GLIOBLASTOMA. CAS  PubMed  Google Scholar  * Verhaak, R. G. W. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma

characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. _Cancer Cell_ 17, 98–110 (2010). CAS  PubMed  PubMed Central  Google Scholar  * Romo, C. G. et al. Widely metastatic

IDH1-mutant glioblastoma with oligodendroglial features and atypical molecular findings: a case report and review of current challenges in molecular diagnostics. _Diagn. Pathol._ 14, 16

(2019). PubMed  PubMed Central  Google Scholar  * Darmanis, S. et al. Single-cell RNA-Seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. _Cell

Reports_ 21, 1399–1410 (2017). CAS  PubMed  Google Scholar  * Chen, J. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. _Nature_ 488, 522–526 (2012).

CAS  PubMed  PubMed Central  Google Scholar  * Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. _Nature_ 444, 756–760 (2006).

CAS  PubMed  Google Scholar  * Cheng, L. et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. _Cell_ 153, 139–152 (2013). CAS  PubMed 

PubMed Central  Google Scholar  * Schäfer, N. et al. Longitudinal heterogeneity in glioblastoma: moving targets in recurrent versus primary tumors. _J. Transl. Med._ 17, 96 (2019). PubMed 

PubMed Central  Google Scholar  * Li, A. et al. Surface biotinylation of cytotoxic T lymphocytes for in vivo tracking of tumor immunotherapy in murine models. _Cancer Immunol. Immunother._

65, 1545–1554 (2016). CAS  PubMed  PubMed Central  Google Scholar  * O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and

induces adaptive resistance in patients with recurrent glioblastoma. _Sci. Transl. Med._ 9, eaaa0984-2 (2017). Google Scholar  * Memarnejadian, A. et al. PD-1 blockade promotes epitope

spreading in anticancer CD8+ T cell responses by preventing fratricidal death of subdominant clones to relieve immunodomination. _J. Immunol._ 199, 3348–3359 (2017). CAS  PubMed  Google

Scholar  * Mathios, D. et al. Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. _Sci. Transl. Med._ 8, 370ra180 (2016). THIS STUDY (REF. 35)

DEMONSTRATED THAT SYSTEMIC TEMOZOLOMIDE INDUCED IMMUNOSUPPRESSION THAT PREVENTED THE EFFECTIVENESS OF PD-1 BLOCKADE IN A PRECLINICAL MODEL. PubMed  PubMed Central  Google Scholar  *

McGranahan, T., Therkelsen, K. E., Ahmad, S. & Nagpal, S. Current state of immunotherapy for treatment of glioblastoma. _Curr. Treat. Options Oncol._ 20, 24 (2019). PubMed  PubMed

Central  Google Scholar  * Hung, A. L. et al. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. _OncoImmunology_ 7, e1466769 (2018). PubMed  PubMed

Central  Google Scholar  * Kim, J. E. et al. Combination therapy with anti-PD-1, anti-TIM-3, and focal radiation results in regression of murine gliomas. _Clin. Cancer Res._ 23, 124–136

(2017). CAS  PubMed  Google Scholar  * Zeng, J. et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. _Int. J. Radiat. Oncol._

86, 343–349 (2013). THIS STUDY (REF. 39) WAS THE FIRST TO SHOW ACTIVITY OF PD-1 BLOCKADE IN A GLIOMA MODEL. CAS  Google Scholar  * Wu, A. et al. Combination anti-CXCR4 and anti-PD-1

immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment. _J. Neurooncol._ 13, 293 (2019). Google Scholar  * Jackson, C. M. & Lim,

M. Immunotherapy for glioblastoma: playing chess, not checkers. _Clin. Cancer Res._ 24, 4059–4061 (2018). CAS  PubMed  Google Scholar  * Cloughesy, T. F. et al. Neoadjuvant anti-PD-1

immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. _Nat. Med._ 25, 477–486 (2019). CAS  PubMed  PubMed Central  Google

Scholar  * Schalper, K. A. et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. _Nat. Med._ 25, 470–476 (2019). CAS  PubMed  Google Scholar  *

Bauer, H.-C., Krizbai, I. A., Bauer, H. & Traweger, A. “You Shall Not Pass”—tight junctions of the blood brain barrier. _Front. Neurosci._ 8, 392 (2014). PubMed  PubMed Central  Google

Scholar  * Spector, R. Nutrient transport systems in brain: 40 years of progress. _J. Neurochem._ 111, 315–320 (2009). CAS  PubMed  Google Scholar  * Coureuil, M., Lécuyer, H., Bourdoulous,

S. & Nassif, X. A journey into the brain: insight into how bacterial pathogens cross blood-brain barriers. _Nat. Rev. Microbiol._ 15, 149–159 (2017). CAS  PubMed  Google Scholar  *

Jackson, C. M., Lim, M. & Drake, C. G. Immunotherapy for brain cancer: recent progress and future promise. _Clin. Cancer Res._ 20, 3651–3659 (2014). PubMed  PubMed Central  Google

Scholar  * Hutter, G. et al. Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma. _Proc. Natl Acad. Sci. USA_ 116, 997–1006 (2019). CAS  PubMed 

PubMed Central  Google Scholar  * Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. _Nat. Med._ 23, 1018–1027 (2017). CAS  PubMed  Google Scholar  *

Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. _Science_ 308, 1314–1318 (2005). CAS  PubMed  Google

Scholar  * Tang, Y. & Le, W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. _Mol. Neurobiol._ 53, 1181–1194 (2016). CAS  PubMed  Google Scholar  * Ransohoff, R.

M. & Cardona, A. E. The myeloid cells of the central nervous system parenchyma. _Nature_ 468, 253–262 (2010). CAS  PubMed  Google Scholar  * Brabb, T. et al. In situ tolerance within

the central nervous system as a mechanism for preventing autoimmunity. _J. Exp. Med._ 192, 871–880 (2000). CAS  PubMed  PubMed Central  Google Scholar  * Na, S.-Y. et al. Oligodendrocytes

enforce immune tolerance of the uninfected brain by purging the peripheral repertoire of autoreactive CD8+ T cells. _Immunity_ 37, 134–146 (2012). CAS  PubMed  Google Scholar  * Klein, R. S.

et al. IFN-inducible protein 10/CXC chemokine ligand 10-independent induction of experimental autoimmune encephalomyelitis. _J. Immunol._ 172, 550–559 (2004). CAS  PubMed  Google Scholar  *

Sandrone, S., Moreno-Zambrano, D., Kipnis, J. & van Gijn, J. A. (delayed) history of the brain lymphatic system. _Nat. Med._ 25, 538–540 (2019). CAS  PubMed  Google Scholar  * Cserr, H.

F., Harling-Berg, C. J. & Knopf, P. M. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. _Brain Pathol._ 2, 269–276 (1992).

CAS  PubMed  Google Scholar  * Laman, J. D. & Weller, R. O. Drainage of cells and soluble antigen from the CNS to regional lymph nodes. _J. Neuroimmune Pharmacol._ 8, 840–856 (2013).

PubMed  PubMed Central  Google Scholar  * Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. _Nature_ 523, 337–341 (2015). THIS STUDY (REF.

59) DESCRIBED LYMPHATIC CHANNELS PARALLELING THE DURAL VENOUS SINUSES AS THE MAJOR ROUTE OF ANTIGEN EGRESS FROM THE CNS. CAS  PubMed  PubMed Central  Google Scholar  * Da Mesquita, S. et al.

Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. _Nature_ 560, 185–191 (2018). PubMed  PubMed Central  Google Scholar  * Da Mesquita, S., Fu, Z. & Kipnis,

J. The meningeal lymphatic system: a new player in neurophysiology. _Neuron_ 100, 375–388 (2018). PubMed  PubMed Central  Google Scholar  * Han, S. et al. Tumour-infiltrating CD4+ and CD8+

lymphocytes as predictors of clinical outcome in glioma. _Br. J. Cancer_ 110, 2560–2568 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Bouffet, E. et al. Immune checkpoint inhibition

for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. _J. Clin. Oncol._ 34, 2206–2211 (2016). CAS  PubMed  Google Scholar  * Mitchell, D. A.

et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. _Nature_ 519, 366–369 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Weiss, T.,

Weller, M., Guckenberger, M., Sentman, C. L. & Roth, P. NKG2D-based CAR T cells and radiotherapy exert synergistic efficacy in glioblastoma. _Cancer Res._ 78, 1031–1043 (2018). CAS 

PubMed  Google Scholar  * Tomaszewski, W., Sanchez-Perez, L., Gajewski, T.F. & Sampson, J.H. Brain tumor microenvironment and host state: implications for immunotherapy. _Clin. Cancer

Res_. https://doi.org/10.1158/1078-0432.CCR-18-1627 (2019). PubMed  PubMed Central  Google Scholar  * Jackson, C. M. et al. Systemic tolerance mediated by melanoma brain tumors is reversible

by radiotherapy and vaccination. _Clin. Cancer Res._ 22, 1161–1172 (2016). THIS STUDY (REF. 67) SHOWED THAT TUMOR LOCATION IS AN INDEPENDENT MEDIATOR OF SYSTEMIC IMMUNOSUPPRESSION THROUGH

MULTIPLE MECHANISMS, INCLUDING DELETION AND TOLERANCE OF TUMOR ANTIGEN-DIRECTED T CELLS. CAS  PubMed  Google Scholar  * Chongsathidkiet, P. et al. Sequestration of T cells in bone marrow in

the setting of glioblastoma and other intracranial tumors. _Nat. Med._ 24, 1459–1468 (2018). THIS STUDY (REF. 68) ADDRESSED THE LONG-STANDING QUESTION OF HOW GBMS INDUCE LYMPHOPENIA BY

DEMONSTRATING THAT T CELLS ARE SEQUESTERED IN THE BONE MARROW OF PATIENTS WITH GBM AND ANIMALS WITH BRAIN TUMORS OF OTHER PATHOLOGIES. CAS  PubMed  PubMed Central  Google Scholar  * Patel,

A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. _Science_ 344, 1396–1401 (2014). CAS  PubMed  PubMed Central  Google Scholar  * McLendon, R.

et al. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. _Nature_ 455, 1061–1068 (2008). CAS  Google Scholar  *

Qazi, M. A. et al. Intratumoral heterogeneity: pathways to treatment resistance and relapse in human glioblastoma. _Ann. Oncol._ 28, 1448–1456 (2017). CAS  PubMed  Google Scholar  * Wang,

Q. et al. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. _Cancer Cell_ 32, 42–56.e6 (2017). PubMed  PubMed

Central  Google Scholar  * Sottoriva, A. et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. _Proc. Natl Acad. Sci. USA_ 110, 4009–4014 (2013). CAS 

PubMed  PubMed Central  Google Scholar  * McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. _Science_ 351, 1463–1469

(2016). THIS STUDY (REF. 74) FOUND THAT HIGH-QUALITY CLONAL NEOANTIGENS ARE CRITICAL FOR RESPONSE TO IMMUNE CHECKPOINT BLOCKADE. CAS  PubMed  PubMed Central  Google Scholar  * Łuksza, M. et

al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. _Nature_ 551, 517–520 (2017). PubMed  PubMed Central  Google Scholar  * Balachandran, V. P. et

al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. _Nature_ 551, 512–516 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Brennan, C. W. et

al. The somatic genomic landscape of glioblastoma. _Cell_ 155, 462–477 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Sampson, J. H. et al. Immunologic escape after prolonged

progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. _J. Clin. Oncol._ 28, 4722–4729 (2010). PubMed

  PubMed Central  Google Scholar  * Wood, M. D., Reis, G. F., Reuss, D. E. & Phillips, J. J. Protein analysis of glioblastoma primary and posttreatment pairs suggests a mesenchymal shift

at recurrence. _J. Neuropathol. Exp. Neurol._ 75, 925–935 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Liau, L. M. et al. First results on survival from a large phase 3 clinical

trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. _J. Transl. Med._ 16, v1–v2 (2018). Google Scholar  * Danilova, L. et al. The mutation-associated neoantigen

functional expansion of specific T cells (MANAFEST) assay: a sensitive platform for monitoring antitumor immunity. _Cancer Immunol. Res._ 6, 888–899 (2018). CAS  PubMed  PubMed Central 

Google Scholar  * Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. _Nature_ 565, 234–239 (2019). CAS  PubMed  Google Scholar  *

Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. _Nature_ 565, 240–245 (2019). CAS  PubMed  Google Scholar  * Desjardins, A. et al. Recurrent

glioblastoma treated with recombinant poliovirus. _N. Engl. J. Med._ 379, 150–161 (2018). CAS  PubMed  PubMed Central  Google Scholar  * Lang, F. F. et al. Phase I study of DNX-2401

(Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. _J. Clin. Oncol._ 36, 1419–1427 (2018). CAS  PubMed  PubMed Central  Google

Scholar  * Cloughesy, T. F. et al. Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. _Neuro-oncol._ 20, 1383–1392 (2018). CAS  PubMed 

PubMed Central  Google Scholar  * Brown, M. C. et al. Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen–specific CTLs.

_Sci. Transl. Med._ 9, eaan4220-2 (2017). THIS STUDY (REF. 87) DEMONSTRATED THAT TREATMENT WITH AN ONCOLYTIC POLIOVIRUS REPROGRAMS DCS, RELEASES DAMAGE- OR PATHOGEN-ASSOCIATED MOLECULAR

PATTERNS, AND GENERATES SUSTAINED CYTOTOXIC RESPONSES. Google Scholar  * Grossman, S. A. et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide.

_Clin. Cancer Res._ 17, 5473–5480 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Maxwell, R. et al. Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for

tumor histologies located within or outside the central nervous system. _OncoImmunology_ 7, e1500108 (2018). PubMed  PubMed Central  Google Scholar  * Giles, A. J. et al.

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. _J. Immunother. Cancer_ 6, 235–232 (2018). Google Scholar  * Topalian, S. L., Drake, C. G. &

Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. _Cancer Cell_ 27, 450–461 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Garcia-Diaz, A.

et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. _Cell Reports_ 19, 1189–1201 (2017). CAS  PubMed  Google Scholar  * Koyama, S. et al. Adaptive resistance

to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. _Nat. Commun._ 7, 10501 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Woroniecka, K.

et al. T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma. _Clin. Cancer Res._ 24, 4175–4186 (2018). THIS STUDY (REF. 94) DELINEATES MECHANISMS OF ADAPTIVE

RESISTANCE IN GLIOBLASTOMA AND DESCRIBES A SEVERE STATE OF EXHAUSTION AMONG TUMOR-INFILTRATING T CELLS. CAS  PubMed  PubMed Central  Google Scholar  * Bauer, C. et al. Prevailing over T cell

exhaustion: New developments in the immunotherapy of pancreatic cancer. _Cancer Lett._ 381, 259–268 (2016). CAS  PubMed  Google Scholar  * Johanns, T. M. et al. Immunogenomics of

hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. _Cancer Discov._ 6, 1230–1236 (2016). PubMed  PubMed Central  Google

Scholar  * Chen, Z. & Hambardzumyan, D. Immune microenvironment in glioblastoma subtypes. _Front. Immunol._ 9, 1004 (2018). PubMed  PubMed Central  Google Scholar  * Mantovani, A.,

Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. _Nat. Rev. Clin. Oncol._ 14, 399–416 (2017). CAS  PubMed  PubMed

Central  Google Scholar  * Takenaka, M. C. et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. _Nat. Neurosci._ 22, 729–740 (2019). CAS  PubMed 

PubMed Central  Google Scholar  * Engler, J. R. et al. Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas. _PLoS One_ 7, e43339 (2012). CAS 

PubMed  PubMed Central  Google Scholar  * Naeini, K. M. et al. Identifying the mesenchymal molecular subtype of glioblastoma using quantitative volumetric analysis of anatomic magnetic

resonance images. _Neuro Oncol._ 15, 626–634 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Pagès, F. et al. International validation of the consensus Immunoscore for the

classification of colon cancer: a prognostic and accuracy study. _Lancet_ 391, 2128–2139 (2018). PubMed  Google Scholar  * Zhu, X., Fujita, M., Snyder, L. A. & Okada, H. Systemic

delivery of neutralizing antibody targeting CCL2 for glioma therapy. _J. Neurooncol._ 104, 83–92 (2011). CAS  PubMed  Google Scholar  * Elmore, M. R. P. et al. Colony-stimulating factor 1

receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. _Neuron_ 82, 380–397 (2014). CAS  PubMed  PubMed Central  Google Scholar  *

Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. _Nat. Med._ 19, 1264–1272 (2013). CAS  PubMed  PubMed Central  Google Scholar  *

Quail, D. F. et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. _Science_ 352, aad3018 (2016). PubMed  PubMed Central  Google Scholar  *

Butowski, N. et al. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II

study. _Neuro Oncol._ 18, 557–564 (2016). PubMed  Google Scholar  * Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. _Nat. Rev. Immunol._ 3,

133–146 (2003). CAS  PubMed  Google Scholar  * Wang, Y. et al. Polymeric nanoparticles promote macrophage reversal from M2 to M1 phenotypes in the tumor microenvironment. _Biomaterials_ 112,

153–163 (2017). CAS  PubMed  Google Scholar  * Zhu, H. et al. Surgical debulking promotes recruitment of macrophages and triggers glioblastoma phagocytosis in combination with CD47 blocking

immunotherapy. _Oncotarget_ 8, 12145–12157 (2017). PubMed  PubMed Central  Google Scholar  * Zhang, M. et al. Anti-CD47 treatment stimulates phagocytosis of glioblastoma by M1 and M2

polarized macrophages and promotes M1 polarized macrophages in vivo. _PLoS One_ 11, e0153550–e0153552 (2016). PubMed  PubMed Central  Google Scholar  * Feng, M. et al. Macrophages eat cancer

cells using their own calreticulin as a guide: roles of TLR and Btk. _Proc. Natl Acad. Sci. USA_ 112, 2145–2150 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Sosa, R. A., Murphey,

C., Ji, N., Cardona, A. E. & Forsthuber, T. G. The kinetics of myelin antigen uptake by myeloid cells in the central nervous system during experimental autoimmune encephalomyelitis. _J.

Immunol._ 191, 5848–5857 (2013). CAS  PubMed  Google Scholar  * Karman, J., Ling, C., Sandor, M. & Fabry, Z. Initiation of immune responses in brain is promoted by local dendritic cells.

_J. Immunol._ 173, 2353–2361 (2004). CAS  PubMed  Google Scholar  * Ursu, R. et al. Intracerebral injection of CpG oligonucleotide for patients with de novo glioblastoma-A phase II

multicentric, randomised study. _Eur. J. Cancer_ 73, 30–37 (2017). CAS  PubMed  Google Scholar  * Carpentier, A. et al. Intracerebral administration of CpG oligonucleotide for patients with

recurrent glioblastoma: a phase II study. _Neuro-oncol._ 12, 401–408 (2010). CAS  PubMed  PubMed Central  Google Scholar  * Garzon-Muvdi, T. et al. Dendritic cell activation enhances

anti-PD-1 mediated immunotherapy against glioblastoma. _Oncotarget_ 9, 20681–20697 (2018). PubMed  PubMed Central  Google Scholar  * Anagnostou, V. et al. Evolution of neoantigen landscape

during immune checkpoint blockade in non-small cell lung cancer. _Cancer Discov._ 7, 264–276 (2017). CAS  PubMed  Google Scholar  * Rosenthal, R. et al. The TRACERx consortium et al.

Neoantigen-directed immune escape in lung cancer evolution. _Nature_ 567, 479–485 (2019). CAS  PubMed  PubMed Central  Google Scholar  * Verdegaal, E. M. E. et al. Neoantigen landscape

dynamics during human melanoma-T cell interactions. _Nature_ 536, 91–95 (2016). CAS  PubMed  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Christopher M. Jackson, John Choi & Michael Lim Authors * Christopher M. Jackson View author

publications You can also search for this author inPubMed Google Scholar * John Choi View author publications You can also search for this author inPubMed Google Scholar * Michael Lim View

author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Michael Lim. ETHICS DECLARATIONS COMPETING INTERESTS 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. ADDITIONAL INFORMATION

PEER REVIEW INFORMATION Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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THIS ARTICLE CITE THIS ARTICLE Jackson, C.M., Choi, J. & Lim, M. Mechanisms of immunotherapy resistance: lessons from glioblastoma. _Nat Immunol_ 20, 1100–1109 (2019).

https://doi.org/10.1038/s41590-019-0433-y Download citation * Received: 29 April 2019 * Accepted: 22 May 2019 * Published: 29 July 2019 * Issue Date: September 2019 * DOI:

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