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Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma.

ABSTRACT: Primary brain tumors, such as glioblastoma (GBM), are remarkably resistant to immunotherapy, even though pre-clinical models suggest effectiveness. To understand this better in patients, here we take advantage of our recent neoadjuvant treatment paradigm to map the infiltrating immune cell landscape of GBM and how this is altered following PD-1 checkpoint blockade using high dimensional proteomics, single cell transcriptomics, and quantitative multiplex immunofluorescence. Neoadjuvant PD-1 blockade increases T cell infiltration and the proportion of a progenitor exhausted population of T cells found within the tumor. We identify an early activated and clonally expanded CD8+ T cell cluster whose TCR overlaps with a CD8+ PBMC population. Distinct changes are also observed in conventional type 1 dendritic cells that may facilitate T cell recruitment. Macrophages and monocytes still constitute the majority of infiltrating immune cells, even after anti-PD-1 therapy. Interferon-mediated changes in the myeloid population are consistently observed following PD-1 blockade; these also mediate an increase in chemotactic factors that recruit T cells. However, sustained high expression of T-cell-suppressive checkpoints in these myeloid cells continue to prevent the optimal activation of the tumor infiltrating T cells. Therefore, future immunotherapeutic strategies may need to incorporate the targeting of these cells for clinical benefit.

SUBMITTER: Lee AH

PROVIDER: S-EPMC8626557 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma.

Lee Alexander H AH Sun Lu L Mochizuki Aaron Y AY Reynoso Jeremy G JG Orpilla Joey J Chow Frances F Kienzler Jenny C JC Everson Richard G RG Nathanson David A DA Bensinger Steven J SJ Liau Linda M LM Cloughesy Timothy T Hugo Willy W Prins Robert M RM

Nature communications 20211126 1

Primary brain tumors, such as glioblastoma (GBM), are remarkably resistant to immunotherapy, even though pre-clinical models suggest effectiveness. To understand this better in patients, here we take advantage of our recent neoadjuvant treatment paradigm to map the infiltrating immune cell landscape of GBM and how this is altered following PD-1 checkpoint blockade using high dimensional proteomics, single cell transcriptomics, and quantitative multiplex immunofluorescence. Neoadjuvant PD-1 block ...[more]

PMID: 34836966

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Project description:PurposeThe treatment of glioblastoma (GBM) poses challenges. The use of immune checkpoint inhibition (ICI) has been disappointing as GBM is characterized by low mutational burden and low T-cell infiltration. The combination of ICI with other treatment modalities may improve efficacy.Patient and methodsPatients with recurrent GBM were treated with avelumab, a human IgG1 antibody directed against PD-L1 (part A), or avelumab within a week after laser interstitial thermal therapy (LITT) and continuation of avelumab (part B). Bevacizumab was allowed to be combined with ICI to spare steroid use. The primary objective was to characterize the tolerability and safety of the regimens. The secondary objectives included overall survival, progression-free survival (PFS), signatures of plasma analytes, and immune cells.ResultsA total of 12 patients (median age 64; range, 37-73) enrolled, five in part A and seven in part B. Two serious adverse events occurred in the same patient, LITT treated, not leading to death. The median survival from enrollment was 13 months [95% confidence interval (CI), 4-16 months] with no differences for part A or B. The median PFS was 3 months (95% CI, 1.5-4.5 months). The decrease in MICA/MICB, γδT cells, and CD4+ T cell EMRA correlated with prolonged survival.ConclusionsAvelumab was generally well tolerated. Adding bevacizumab to ICI may be beneficial by lowering cytokine and immune cell expression. The development of this combinatorial treatment warrants further investigation. Exploring the modulation of adaptive and innate immune cells and plasma analytes as biomarker signatures may instruct future studies in this dismal refractory disease.SignificanceOur phase I of PD-L1 inhibition combined with LITT and using bevacizumab to spare steroids had a good safety profile for recurrent GBM. Developing combinatory treatment may help outcomes. In addition, we found significant immune modulation of cytokines and immune cells by bevacizumab, which may enhance the effect of ICI.

Project description:BackgroundAntibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade.MethodsIn this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses.ResultsNeoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab.ConclusionsNeoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute-Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621 .).

Project description:The differentiation and effector function of tumor infiltrating lymphocytes and macrophages in the tumor microenvironment is critical for productive anti-tumor immune responses, although direct evidence for this remains poorly characterized in brain cancer patients. Using mass cytometry, single-cell RNA sequencing, and quantitative multiplex immunofluorescence, we comprehensively characterized the phenotype and single-cell transcriptome of myeloid cells and T lymphocytes that infiltrated malignant gliomas, and identified how such populations changed following neoadjuvant PD-1 checkpoint blockade in recurrent glioblastoma patients. Cells of the myelo-monocytic lineage represented approximately three quarters of the immune cell infiltrate, with T lymphocytes representing the next major immune cell subset by density and percentage, but following neoadjuvant PD-1 antibody blockade, the ratio of myeloid cells to T cells significantly decreased. We then used single-cell RNA sequencing to comprehensively define the transcriptional profiles of lymphoid and myeloid populations in these tumors. Recurrent GBM patients treated with neoadjuvant PD-1 checkpoint inhibition possessed a greater fraction of CD8+ T cells with an effector T cell transcriptional program. The increased effector T cell populations were associated with the distinct upregulation of the chemokines, CXCL9 and CXCL10 by an interferon-responsive macrophage cluster. Importantly, we also identified that neoadjuvant PD-1 blockade was associated with significantly increased cellular interactions specifically between CD8+ T cells and tumor associated macrophages within the tumor microenvironment. Together, these findings suggest that effector T cell infiltration and differentiation are increased with neoadjuvant PD-1 blockade but impeded by adaptive resistance and immunosuppression from tumor associated macrophages. Future therapeutic strategies to target this dominant immunosuppressive myeloid cell population may be needed to achieve true, therapeutic interventions in this patient population.

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Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma.

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Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma.

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