Glioblastoma (GBM) is inevitably refractory to surgery and chemoradiation. The hope for immunotherapy has yet to be realised in the treatment of GBM. Immune checkpoint blockade antibodies, particularly those targeting the Programme death 1 (PD-1)/PD-1 ligand (PD-L1) pathway, have improved the prognosis in a range of cancers. However, its use in combination with chemoradiation or as monotherapy has proved unsuccessful in treating GBM. This review focuses on our current knowledge of barriers to immunotherapy success in treating GBM, such as diminished pre-existing anti-tumour immunity represented by low levels of PD-L1 expression, low tumour mutational burden and a severely exhausted T-cell tumour infiltrate. Likewise, systemic T-cell immunosuppression is seen driven by tumoural factors and corticosteroid use. Furthermore, unique anatomical differences with primary intracranial tumours such as the blood-brain barrier, the type of antigen-presenting cells and lymphatic drainage contribute to differences in treatment success compared to extracranial tumours. There are, however, shared characteristics with those known in other tumours such as the immunosuppressive tumour microenvironment. We conclude with a summary of ongoing and future immune combination strategies in GBM, which are representative of the next wave in immuno-oncology therapeutics.

2019) Impaired circulating myeloid CD1c+ dendritic cell function in human glioblastoma is restored by p38 inhibition -implications for the next generation of DC vaccines, OncoImmunology, 8:7, e1593803, ABSTRACT Current treatments for glioblastoma (GBM) have limited efficacy and significant morbidity and therefore new strategies are urgently needed. Dendritic cells have the power to create anti-tumor immune responses. The greater potency of circulating dendritic cells (DC) over laboratory-generated monocytederived DC makes them exciting new immunotherapeutic candidates. To determine the immune status of GBM patients we initially investigated the frequency and function of circulating DC subsets. Furthermore, we tested the therapeutic potential of inhibiting the p38 mitogen-activated protein kinase pathway (p38i) in circulating DC to overcome DC dysfunction.GBM patients (n = 16) had significantly reduced numbers of the major myeloid circulating dendritic cell (cDC2) and plasmacytoid DC vs healthy controls; 1736 vs 4975 (p = 0.028) and 893 vs 2287 cells/mL (P = <0.001) respectively. This inversely correlated with dexamethasone (Dex) dose in a log-linear model, and disease status. Patients' cDC2 were immature with impaired interleukin (IL)-12 secretion, reduced IL-12:IL-10 ratio, and low HLA-DR and CD86 expression. Exposure of healthy donor cDC2 to Dex or GBM cell lysate resulted in a similar low IL-12:IL-10 ratio. Inhibition of p38 restored the IL-12:IL-10 balance in Dex or tumor lysate-conditioned healthy cDC2 and enhanced T-cell proliferation and interferon-gamma (IFNγ) production. Importantly, patient-derived cDC2 showed a similar reversal of DC dysfunction with p38i. This study demonstrates the therapeutic potential of developing the next generation of DC vaccines using enhanced p38i-conditioned cDC2. We will therefore shortly embark on a clinical trial of adoptively transferred, p38 MAPKinhibited cDC2 in adults with GBM. ARTICLE HISTORY

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The balance of innate signaling through adaptor proteins such as MyD88 and TRIF is critical in directing the pattern of inflammatory responses following exposure to endogenous adjuvants. While innate stimuli can cause inflammation that supports adaptive immunity, cancer myeloid cells can be pre-polarized such that the same inflammatory signals cause myeloid cells to suppress adaptive immune responses. We aim to investigate the signals regulating type I IFN secretion by innate immune cells in tumors in order to improve type I IFN secretion, activation of innate immune cells, direct macrophage polarization and improve CD8+ T cell mediated anti-tumor immunity. To better understand the role of MyD88-mediated signaling in driving response to innate adjuvants released following RT in solid tumors, we developed MyD88 conditional knockout mouse models. MyD88 was deleted specifically in CD11c expressing dendritic cells (DC), Lck expressing T cells, or Lyz2 expressing myeloid cells that include macrophages, monocytes and granulocytes. Mice bearing pancreatic tumors (Panc02-SIY or PK5L1940) were randomized to no treatment or 16 Gy CT-guided RT and followed for treatment responses. Lyz2-Cre/MyD88fl/fl mice demonstrated improved responses to RT in pancreatic tumors as compared to control MyD88fl/fl mice, or Lck-Cre mice. The improved responses in Lyz2-Cre/MyD88fl/fl mice were shown to be dependent on CD8+ T cells as well as on type I IFN signaling. To analyze mechanisms of response, tumors were digested into a single cell suspension and CD45+ cells were isolated for single cell sequencing three days post-RT. Lyz2-Cre/MyD88fl/fl mice showed diminished Th1 and Th2-type T cells and had a higher M1/TAM ratio compared to MyD88fl/fl mice. Loss of MyD88 in myeloid cells resulted in increased activation of IFN-dependent transcriptional responses in multiple immune cell populations in the tumor. To model responses ex vivo, bone marrow-derived macrophages (BMDMs) were activated with lipopolysaccharide (LPS) or a synthetic cyclic dinucleotide (CDA) for analysis of cytokine secretion in either monolayer or 3D spheroid culture conditions. BMDM derived from Lyz2-Cre/MyD88fl/fl cultured as a monolayer showed significantly altered secretion of TNF-α, IL-10 and IL-6 on activation with LPS as compared to controls. Preliminary data obtained from 3D spheroid culture systems demonstrated that 3D interactions between cancer cells and macrophages resulted in a significant increase in BMDM co-stimulatory phenotype following activation with innate stimuli compared to 2D cultures. These data suggest that conventional innate signaling through MyD88 in myeloid populations suppresses IFN production and adaptive immune control of irradiated tumors. 3D cultures are an effective tool to study cellular interactions ex vivo and screen novel interventions prior to in vivo translation. Citation Format: Aanchal Preet Kaur, Terry R. Medler, Tiffany C. Blair, Alejandro F. Alice, Megan R. Ball, Alexa K. Dowdell, Brian D. Piening, Marka R. Crittenden, Michael J. Gough. Deciphering the role of MyD88 signaling pathway in regulating type I IFN-mediated responses to radiation therapy in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6410.

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