Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma

Simonds, Erin F.; Lu, Edbert D; Badillo, O.; Karimi, Shokoufeh; Liu, Eric V; Tamaki, Whitney; Rancan, Chiara; Downey, Kira; Stultz, Jacob; Sinha, Mala; McHenry, Lauren; Nasholm, Nicole; Chuntova, Pavlina; Sundström, Anders; Genoud, Vassilis; Shahani, Shilpa; Wang, Leo D.; Brown, Christine E.; Walker, Paul R; Swartling, Fredrik J.; Fong, Lawrence; Okada, Hideho; Weiss, William A.; Hellström, Mats

doi:10.1136/jitc-2020-002181

Cited by 63 publications

(51 citation statements)

References 48 publications

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“…To verify the immune competence of these mouse models, we first characterized the TIME of the primary IUE tumors by performing CyTOF mass cytometry on extracted whole tumor tissue, as described previously. 30 Analysis of gated immune cell populations demonstrated that both histone wildtype and mutant IUE tumors consisted predominantly of myeloid cells, specifically microglia and macrophages, and very few lymphocytes, corresponding to what has previously been observed in human DMG autopsy tissue ( Figure 3 , Supplementary Figure S7 ). 12 , 13 We subsequently analyzed the TIME in our secondary allograft models by staining for these immune cell populations by IHC and IF and comparing these to analogous human DMG tissues.…”

Section: Resultssupporting

confidence: 75%

Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma

Chatinier

Meel

Das

et al. 2022

Neuro-Oncology Advances

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Background Diffuse midline gliomas (DMG) are highly malignant incurable pediatric brain tumors. A lack of effective treatment options highlights the need to investigate novel therapeutic strategies. This includes the use of immunotherapy, which has shown promise in other hard-to-treat tumors. To facilitate preclinical immunotherapeutic research, immunocompetent mouse models that accurately reflect the unique genetic, anatomical, and histological features of DMG patients are warranted. Methods We established cell cultures from primary DMG mouse models (C57BL/6) that were generated by brainstem targeted intra-uterine electroporation (IUE). We subsequently created allograft DMG mouse models by orthotopically implanting these tumor cells into syngeneic mice. Immunohistochemistry and -fluorescence, mass cytometry, and cell-viability assays were then used to verify that these murine tumors recapitulated human DMG. Results We generated three genetically distinct allograft models representing histone 3 wildtype (H3 WT) and K27M-mutant DMG (H3.3 K27M and H3.1 K27M). These allograft models recapitulated the histopathologic phenotype of their human counterparts, including their diffuse infiltrative growth and expression of DMG-associated antigens. These murine pontine tumors also exhibited an immune microenvironment similar to human DMG, characterized by considerable myeloid cell infiltration and a paucity of T-lymphocytes and NK cells. Finally, we show that these murine DMG cells display similar sensitivity to histone deacetylase (HDAC) inhibition as patient-derived DMG cells. Conclusions We created and validated an accessible method to generate immunocompetent allograft models reflecting different subtypes of DMG. These models adequately recapitulated the histopathology, immune microenvironment, and therapeutic response of human DMG, providing useful tools for future preclinical studies.

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Section: Resultssupporting

confidence: 75%

Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma

Chatinier

Meel

Das

et al. 2022

Neuro-Oncology Advances

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“…With the advent of high-throughput multiplexed analytical technologies, peripheral blood is now suitable for deeper immune profiling. As peripheral blood sampling is readily available, minimally invasive, and repeatable, the use of blood-based immune biomarkers can compensate for the abovementioned limitations of tissue-based immune biomarkers during cancer immunotherapy [11,15,[18][19][20][21][22][23]. This review aimed to summarize pivotal findings related to blood-based immune biomarkers in patients with solid cancer treated with ICIs (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Peripheral Blood-Based Biomarkers for Immune Checkpoint Inhibitors

Chon

Kim

2021

IJMS

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As cancer immunotherapy using immune checkpoint inhibitors (ICIs) is rapidly evolving in clinical practice, it is necessary to identify biomarkers that will allow the selection of cancer patients who will benefit most or least from ICIs and to longitudinally monitor patients′ immune responses during treatment. Various peripheral blood-based immune biomarkers are being identified with recent advances in high-throughput multiplexed analytical technologies. The identification of these biomarkers, which can be easily detected in blood samples using non-invasive and repeatable methods, will contribute to overcoming the limitations of previously used tissue-based biomarkers. Here, we discuss the potential of circulating immune cells, soluble immune and inflammatory molecules, circulating tumor cells and DNA, exosomes, and the blood-based tumor mutational burden, as biomarkers for the prediction of immune responses and clinical benefit from ICI treatment in patients with advanced cancer.

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“…Gene set enrichment analysis and KEGG pathway analysis both confirmed that IFNγ response, antigen-processing and presentation machinery, along with multiple proinflammatory signatures, were significantly enriched after IDH1 R132H inhibition compared with the control ( figure 6B ). 21 As Pd-l1 is known to be upregulated in response to IFNγ signaling and PD-L1 + myeloid populations are enriched in gliomas, 22 we used FC to evaluate the in vivo protein expression of HLA-DR and PD-L1 on the surface of immune cells in the TME and observed that both molecules were significantly upregulated in response to AG-881 treatment ( figure 6C ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma

Chuntova

Yamamichi

Chen

et al. 2022

J Immunother Cancer

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BackgroundLong-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the ‘cold’ tumor phenotype. Inhibiting D-2HG production presents an opportunity to generate a robust antitumor response following tumor antigen vaccination and immune checkpoint blockade.MethodsAn IDH1R132H glioma model was created in syngeneic HLA-A2/HLA-DR1-transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1R132H mutation-derived neoepitope. The effects of an orally available inhibitor of mutant IDH1 and IDH2, AG-881, were evaluated as monotherapy and in combination with the IDH1R132H peptide vaccination or anti-PD-1 immune checkpoint blockade.ResultsThe HLA-A2/HLA-DR1-syngeneic IDH1R132H cell line expressed the IDH1 mutant protein and formed D-2HG producing orthotopic gliomas in vivo. Treatment of tumor-bearing mice with AG-881 resulted in a reduction of D-2HG levels in IDH1R132H glioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1R132H gliomas. AG-881 monotherapy suppressed the progression of IDH1R132H gliomas in a CD4+ and CD8+ cell-dependent manner, enhanced proinflammatory IFNγ-related gene expression, and increased the number of CD4+ tumor-infiltrating T-cells. Prophylactic vaccination with the HLA-DR1-restricted IDH1R132H peptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1R132H and DR1-IDH1R132H peptides in combination with the IDH inhibitor significantly prolonged survival. Finally, tumor-bearing mice treated with both AG-881 and a PD-1 blocking antibody demonstrated improved survival when compared with either treatment alone.ConclusionThe development of effective IDH1R132H-targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our HLA-A2/HLA-DR1-syngeneic IDH1R132H glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.

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Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma

Cited by 63 publications

References 48 publications

Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma

Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma

Peripheral Blood-Based Biomarkers for Immune Checkpoint Inhibitors

Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma

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