Characterization of PD‐1 upregulation on tumor‐infiltrating lymphocytes in human and murine gliomas and preclinical therapeutic blockade

Dejaegher, Joost; Verschuere, Tina; Vercalsteren, Ellen; Boon, Louis; Cremer, Jonathan; Sciot, Raf; Gool, Stefaan Van; Vleeschouwer, Steven De

doi:10.1002/ijc.30877

Cited by 23 publications

(21 citation statements)

References 44 publications

(75 reference statements)

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“…To characterize the immune exhaustion profile of GBM TILs in comparison with PBLs, we analyzed the following markers: PD-1, Tim-3, KLRG1, CD57, CD39, and CD73. PD-1 proved to be the most strikingly upregulated exhaustion marker on both CD8 þ and CD4 þ TILs, which is in line with a recently published study (40). Expanding on those previous findings, we further demonstrate a significant increase of PD-1 expression on PBLs in patients with rGBM versus patients with pGBM, suggesting an even more pronounced systemic exhaustion in the relapse setting.…”

Section: Discussionsupporting

confidence: 91%

Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes

Mohme

Schliffke

Maire

et al. 2018

Clinical Cancer Research

112

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Immunotherapeutic treatment strategies for glioblastoma (GBM) are under investigation in clinical trials. However, our understanding of the immune phenotype of GBM-infiltrating T cells (tumor-infiltrating lymphocytes; TILs) and changes during disease progression is limited. Deeper insight is urgently needed to therapeutically overcome tumor-induced immune exhaustion. We used flow cytometry and cytokine assays to profile TILs and peripheral blood lymphocytes (PBLs) from patients with GBM, comparing newly diagnosed or recurrent GBM to long-term survivors (LTS) and healthy donors. TCR sequencing was performed on paired samples of newly diagnosed and recurrent GBM. We identified a clear immune signature of exhaustion and clonal restriction in the TILs of patients with GBM. Exhaustion of CD8 TILs was defined by an increased prevalence of PD-1, CD39, Tim-3, CD45RO, HLA-DR marker expression, and exhibition of an effector-/transitional memory differentiation phenotype, whereas KLRG1 and CD57 were underrepresented. Immune signatures were similar in primary and recurrent tumors; however, restricted TCR repertoire clonality and a more activated memory phenotype were observed in TILs from recurrent tumors. Moreover, a reduced cytokine response to PHA stimulation in the blood compartment indicates a dysfunctional peripheral T-cell response in patients with GBM. LTS displayed a distinct profile, with abundant naïve and less exhausted CD8 T cells. TILs and PBLs exhibit contrasting immune profiles, with a distinct exhaustion signature present in TILs. While the exhaustion profiles of primary and recurrent GBM are comparable, TCR sequencing demonstrated a contracted repertoire in recurrent GBM, concomitant with an increased frequency of activated memory T cells in recurrent tumors. .

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Section: Discussionsupporting

confidence: 91%

Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes

Mohme

Schliffke

Maire

et al. 2018

Clinical Cancer Research

112

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“…Similar to the results in the clinic with checkpoint inhibitors for GBM, treatment of mice bearing 005 GSC-derived tumors, representative of immunologically 'cold' tumors, with systemic immune checkpoint antibodies (anti-PD-1 or anti-PD-L1 or anti-CTLA-4) provided only modest prolongation of survival [17]. This contrasts with the results seen with mouse GL261 syngeneic tumors [47][48][49]. Even the combination of two antibodies (anti-PD-1+anti-CTLA-4) was not successful in the 005 GSC model, only delaying tumor progression without cures [17].…”

Section: Immune Checkpointsmentioning

confidence: 60%

Oncolytic Herpes Simplex Virus Immunovirotherapy in Combination with Immune Checkpoint Blockade to Treat Glioblastoma

2018

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Oncolytic viruses, such as oncolytic herpes simplex virus (oHSV), are a new class of cancer therapeutic, which selectively replicate and kill cancer cells, while inducing an inflammatory microenvironment, immunovirotherapy. Recently, an oHSV (talimogene laherparepvec) has been approved for the treatment of advanced melanoma. Glioblastoma (GBM) is an almost always lethal primary tumor in the brain that is highly immunosuppressive, and posited to contain GBM stem-like cells (GSCs). Immune checkpoint blockade has revolutionized therapy for some cancers, but not GBM. We have used a syngeneic GSC-derived orthotopic GBM model (005) to develop immunotherapeutic strategies. Curative therapy required oHSV expressing IL-12 in combination with two checkpoint inhibitors, anti-PD-1 and anti-CTLA-4. This response required CD4 and CD8 T cells, and macrophages in a complex interplay.

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“…In this study, we studied not only which immune checkpoint receptors are expressed on CD8 þ TILs in patients with GBM, but also whether their proliferation can be restored by blocking immune checkpoint receptors. Previous studies have shown increased expression of PD-1 (33)(34)(35)(36), Tim-3 (35)(36)(37), and LAG-3 (36) on CD8 þ TILs in patients with GBM; however, to the best of our knowledge, ex vivo functional assays to reinvigorate CD8 þ TILs by ICI treatment have not yet been performed in GBM.…”

Section: Discussionmentioning

confidence: 95%

Immune Checkpoint Inhibitor-induced Reinvigoration of Tumor-infiltrating CD8+ T Cells is Determined by Their Differentiation Status in Glioblastoma

Park

Kwon

Kim

et al. 2019

Clinical Cancer Research

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Purpose: Immune checkpoint inhibitors (ICI) are used for the treatment of various cancers, but clinical trials of antiprogrammed cell death protein 1 (PD-1) with patients with recurrent glioblastoma (GBM) have failed to show clinical benefits. In this study, we examined the differentiation status of CD8 þ tumor-infiltrating lymphocytes (TIL) from patients with primary GBM and their reinvigoration by ICIs to understand the nature of T-cell exhaustion in GBM.Experimental Design: We isolated TILs from 98 patients with newly diagnosed GBM and examined the expression of immune checkpoint receptors and T-cell transcription factors using flow cytometry. TILs were ex vivo stimulated with anti-CD3 in the presence of anti-PD-1 and/or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and their proliferation assessed.Results: CD8 þ TILs had significantly increased expression of immune checkpoint receptors, including PD-1 and CTLA-4, compared with peripheral blood CD8 þ T cells. Among CD8 þ TILs, PD-1 þ cells exhibited more terminally differentiated phenotypes (i.e., Eomes hi T-bet lo ) than PD-1 À cells. These data were confirmed by analyzing NY-ESO-1 157 -specific CD8 þ TILs. Evaluating the proliferation of CD8 þ TILs after ex vivo stimulation with anti-CD3 and anti-PD-1, we found that proliferation inversely correlated with the percentage of Eomes hi T-bet lo cells among PD-1 þ CD8 þ TILs. When anti-CTLA-4 was used in combination with anti-PD-1, an additional increase in CD8 þ TIL proliferation was observed in patients with low percentages of Eomes hi T-bet lo CD8 þ TILs, who responded well to anti-PD-1 in ex vivo assays, but not in patients with high percentages of Eomes hi T-bet lo CD8 þ TILs, who did not respond to anti-PD-1.Conclusions: In primary GBM, the differentiation status of CD8 þ TILs determines their reinvigoration ability upon ICI treatment.

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Characterization of PD‐1 upregulation on tumor‐infiltrating lymphocytes in human and murine gliomas and preclinical therapeutic blockade

Cited by 23 publications

References 44 publications

Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes

Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes

Oncolytic Herpes Simplex Virus Immunovirotherapy in Combination with Immune Checkpoint Blockade to Treat Glioblastoma

Immune Checkpoint Inhibitor-induced Reinvigoration of Tumor-infiltrating CD8+ T Cells is Determined by Their Differentiation Status in Glioblastoma

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