Abstract Rationale Neuroblastoma is a devastating pediatric malignancy, for which surgical resection is a key factor in long-term survival. However, there are significant challenges in its resection, particularly in high-risk disease, as neuroblastoma encases surrounding critical structures, is often difficult to distinguish from desmoplastic or scar tissue, and can carry occult deposits of disease not readily identified on preoperative imaging or intraoperative visualization. Building on the principles of fluorescent and radio-guided surgery, in combination with the known overexpression of GD2 in neuroblastoma, we sought to develop and optimize 111 In-Dinutuximab-IRDye800, a dual-modality GD2-targeted intraoperative molecular imaging agent, for use in pediatric neuroblastoma to help enhance patient safety while facilitating a more complete resection. Methods Dinutuximab was conjugated to IRDye800 and DTPA, then radiolabeled with Indium-111 to yield 111 In-Dinutuximab-IRDye800. Optimization occurred through ELISA assay to assess binding affinity, fluorescence intensity analysis to determine the optimal fluorescent degree of labeling, and phototoxicity testing through flow cytometry. Rodent models of neuroblastoma were then generated through injection of SK-N-BE(2) human neuroblastoma cells into the left adrenal glands of nude mice or RNU rats. A series of fluorescent and gamma biodistributions was performed, varying the dose, timing, and specific activity of the tracer. Tumor and organ uptake of the tracer was compared with one- or two-way ANOVA as appropriate, with Sidak’s multiple comparison test to compare tumor uptake to individual organs. Once optimization was complete, a clinically significant events study modeled after human clinical trials was performed to evaluate the in vivo capabilities of 111 In-Dinutuximab-IRDye800. Results Increased ratios of IRDye800 per antibody led to decreased binding affinity for GD2 and was associated with formulation instability without significant return on fluorescence intensity. Specific activity of the tracer was not found to impact overall biodistribution of the tracer. A 45-50 µg dose of 111 In-Dinutuximab-IRDye800 with ratios around 1 DTPA and 1-1.5 IRDye800 per antibody imaged 4 days after tracer administration was found to be the optimal combination that maximized detectable tumor-specific signal. In the clinically significant events study mirroring human IMI clinical trials, fluorescent guidance identified additional malignant lesions not originally detected under white light in 64% of rodents. Conclusions 111 In-Dinutuximab-IRDye800 is a dual-modality GD2-targeted intraoperative imaging agent that is well-poised for clinical translation. As it preserves tumor specificity, yields clinically meaningful radiofluorescent signal, and is well-tolerated without adverse events after optimization was completed, it carries the potential to positively impact the safety and completeness of neuroblastoma resection.

Intraoperative molecular imaging (IMI) is an evolving tool that enables targeted real-time visualization and delineation of tissue during surgery. IMI tracers can be fluorescent, radioactive, or dual-labeled. Their integration into the intraoperative setting is supported by several clinical trials, which led to Food and Drug Administration approval for a variety of these agents. Fluorescent tracers enable excellent spatial visualization, whereas radiotracers enable deep tissue detection, and dual-labeled tracers provide both. Novel activatable tracers that leverage properties of the tumor microenvironment are also being developed. Advances in imaging devices now permit IMI usage across diverse platforms, including minimally invasive surgery. Despite the limitations of autofluorescence, false-positive signals, and heterogeneity, the use of IMI continues to broaden in oncologic and nononcologic applications, driven by demonstrated improvements in surgical outcomes. In this review, we highlight the translation of IMI through clinical trials and future directions in IMI-guided surgery.

Abstract Medulloblastoma (MB) is a heterogeneous brain tumor arising in the cerebellum and is the most common malignant pediatric brain tumor. Group 3, one of four molecular MB subgroups (WNT, SHH, Group 3, and Group 4), is the most aggressive and malignant type in children, usually characterized by metastasis at diagnosis. In this study, we identify that SMARCD3/BAF60c (SMARCD3 hereafter), a core component of the SWI/SNF chromatin-remodeling complexes, is highly expressed in Group 3 MB and Purkinje cells (PCs) of the developing cerebellum. Elevated SMARCD3 expression is associated with poorer patient outcomes, MB metastasis, and activation of the Disabled1 (DAB1)-Reelin signaling pathway that is required for PC migration and positioning during cerebellar development. Conditional SMARCD3 deletion in early PCs results in embryonic and early postnatal lethality in mice, and the surviving animals exhibit significant deficits in motor coordination and balance. Immunostaining of SMARCD3 deleted murine cerebellar tissue shows disorganized PC alignment and reduced dendritic branching, confirming the critical role of the SMARCD3-Reelin pathway function in PC migration, positioning, and maturation. These data demonstrate that the SMARCD3-associated SWI/SNF chromatin-remodeling complex regulates Reelin signaling pathway in PC migration and positioning during cerebellar development; however, this neurodevelopmental program is hijacked to promote MB metastatic dissemination. To further understand this mechanism, we analyzed spatiotemporal gene expression and chromatin accessibility data of the human and mouse cerebellum, noting the SMARCD3/Reelin signaling decreased in the mature cerebellum, but is highly upregulated in metastatic medulloblastoma. The study provides compelling functional evidence of SMARCD3 and the associated SWI/SNF complexes’ involvement in cerebellar development, tumor metastasis, and the molecular connections between early brain development and tumorigenesis, offering new rationales for the development of innovative therapies for patients with MB. Citation Format: Yash Patel, Han Zou, Allen Zheng, Anjali Talluru, Nirja Divekar, Chaim Sneiderman, Meghana Dodda, Katie Dietrich, Siheng Chao, Sameer Agnihotri, Gary Kohanbash, Antony Michealraj, Ian Pollack, Baoli Hu. SMARCD3-regulated Purkinje cell migration underlies cerebellar development and group 3 medulloblastoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 629.

Glioblastoma multiforme (GBM) is one of the deadliest types of cancer that occurs in people of all ages; 15 months is the average survival time. While treatments for GBM are mostly unsuccessful, immunotherapy has the potential to be an effective strategy for glioblastoma. However, the immunosuppressive influence of tumor-associated myeloid cells (TAMCs) results in poor responses to immunotherapy. As TAMCs are CD11b-positive, the potential of a radiolabeled αCD11b diabody was investigated to assess immunosuppression mediated by TAMCs in an immunocompetent mouse model of glioblastoma. An αCD11b diabody (Db) was constructed with the VH and VL sequences of an αCD11b IgG that resulted in thermal stability and high affinity. αCD11b Db was conjugated with a cross-bridged chelator, CB-TE1K1P, through click chemistry. The resulting conjugate was radiolabeled with 64Cu and investigated in vitro and in a model of glioblastoma. [64Cu]-Cu-αCD11b Db visualized TAMCs in a syngeneic mouse glioblastoma, achieving optimal uptake within 4 h post administration with a %ID/g of 1.06 and 0.18 for tumor and healthy brain tissue. In correlating molar activity (8.51, 4.26, 2.12, and 1.06 MBq/nmol) with uptake (%ID/g of 0.162, 0.825, 1.06, and 0.445, respectively), we demonstrated that 2.12 MBq/nmol gave optimal uptake, since tracer pharmacokinetics was modulated by αCD11b Db occupation of the CD11b antigen sink. In conclusion, [64Cu]-Cu-αCD11b Db is a high-affinity and stable diabody, which can quantify CD11b-positive TAMCs in the tumor microenvironment, particularly when the molar activity of the administered [64Cu]-Cu-αCD11b Db is optimized for managing the CD11b antigen sink in the spleen, liver, and bone marrow.

e14556 Background: Near-infrared photoimmunotherapy (PIT) is a novel, molecularly targeted cancer therapy. It combines tumor-directed immunotherapy agents with a phthalocyanine dye IR700 to induce rapid cell death upon light activation, while sparing adjacent normal tissue. GD2 is a targetable tumor-associated antigen expressed in neuroblastoma, osteosarcoma and glioblastoma. Dinutuximab, an anti-GD2 monoclonal antibody, has demonstrated clinical efficacy in neuroblastoma immunotherapy. We evaluated the efficacy of Dinutuximab-IR700 as a targeted PIT agent in in vitro models of GD2-expressing tumors. Methods: We synthesized a Dinutuximab-IR700 antibody dye conjugate (ADC) and tested it on human-derived SK-N-BE(2) and NMB6 (neuroblastoma), LM7 and 143B (osteosarcoma), U87 (glioblastoma) and mouse-derived GL261 and SB28 (glioblastoma) cell lines. For PIT, cells were incubated with ADC (15 μg/mL), followed by activation with light at 10-100 J/cm 2 at 150 mW/cm 2 . Controls included untreated, light-only and ADC-only groups, along with apoptosis (camptothecin) and necrosis (H 2 O 2 ) positive controls. Additional ADC doses of 5, 10 and 20 μg/mL were evaluated in neuroblastoma. Cell death was evaluated by Annexin V/Propidium Iodide (PI) flow cytometry, and brightfield/fluorescence microscopy at 24 h and 48 h post-PIT. GD2 expression per cell for each cell line was also quantified by flow cytometry to correlate with PIT response. Results: Dinutuximab-IR700 PIT markedly reduced cancer cell viability in both neuroblastoma cell lines by up to 78%. Light and ADC had dose-dependent effects on cell death, plateauing at 50 J/cm 2 and 15 μg/mL, respectively. PIT efficacy on osteosarcoma cell lines was heterogeneous, with up to 14% cell death observed only in LM7. PIT was not effective in U87, GL261 and SB28 glioblastoma cells, which showed minimal ADC binding on fluorescence microscopy. Cell death by PIT strongly correlated with GD2 expression per cell across tumor cell lines. Light-only and ADC-only groups matched untreated controls. PIT efficacy was similar with different degrees of labeling (2 vs 3 IR700 molecules per Dinutuximab molecule). Annexin V/PI staining indicated apoptosis over necrosis as the primary mode of cell death, supported by microscopy. Dinutuximab-IR800, studied for intraoperative molecular imaging, was ineffective under identical conditions, demonstrating IR700’s unique utility for PIT. Conclusions: GD2-targeted Dinutuximab-IR700 PIT induces profound dose-dependent cytotoxicity across neuroblastoma cell lines, with variable activity in osteosarcoma and none in glioblastoma. The precise mechanism of action of PIT and reasons for its heterogeneous efficacy in different GD2-expressing tumors remain to be elucidated. This represents a novel precision medicine approach to neuroblastoma treatment, particularly for residual disease after surgical resection.

Purpose:To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Methods:Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed. Results:Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline PTPN11 variant; Nineteen of 24 participants (79%) were male. Seventeen (89%) patients with NS developed CNS cancers, including low-grade glioma, (LGG; pure pilocytic/pilomyxoid astrocytoma; n=9) and mixed dysembryoplastic neuroepithelial tumor (DNET; n=6). Five patients incidentally diagnosed did not undergo histological confirmation. Radiological review showed multifocal parenchymal tumors in 9 patients with NS, including histologically confirmed neoplasm (n=2), radiologic progression (n=6), or typical tumoral imaging (n=1). All LGGs in patients with NS and germline PTPN11 variants except one (14/15; 93%) harbored somatic FGFR1 abnormalities. RNA sequencing of 12 tumors detected FGFR1 internal tandem duplication in one patient. Comparison with published data showed a statistically significant association between brain tumor occurrence and PTPN11-related NS, driven by two genotypes: NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly) and c.417G>T (p.Glu139Asp). Ten patients with LGGs, including 7 (41%) with NS, required chemotherapy. After median follow-up of 7.5 years, one patient died of CNS cancer. Conclusion:PTPN11-related NS predisposes to multifocal pure and mixed LGGs confirmed by radiological, histological, and molecular characteristics. Targeting FGFR1-related pathways may provide new treatment approaches for patients with NS and LGGs.

Abstract Diffuse midline glioma (DMG) is a highly aggressive, inoperable pediatric brain tumor that primarily affects children under 10 years of age and is associated with a median survival of only 9 to 12 months. The diffuse and infiltrative growth pattern of DMG, combined with the incidence in infratemporal and brainstem location, precludes surgical and conventional radiological interventions. Current standard-of-care therapies, such as radiation and chemotherapy, offer only temporary symptomatic relief and limited tumor control. While rodent models of DMG exist, therapeutic strategies effective in these systems have repeatedly failed in clinical translation, likely due to fundamental differences in brain size, anatomy, and physiology between rodents and humans. Therefore, there is an urgent need for a more predictive and clinically relevant animal model of DMG. The pig is proposed as an advanced preclinical model for DMG due to its substantial genetic, anatomical (gyroencephalic brain), and physiological similarities with humans, particularly regarding size, brain structures, and neurodevelopment. The large brain size of pigs putatively permits the emergence of tumors that more closely resemble human DMG in both scale and architecture, enabling the development and assessment of clinically relevant surgical, imaging, and interventional strategies. Furthermore, the longer lifespan of pigs supports longitudinal evaluation of tumor progression and therapeutic response. To address this need, an inducible porcine DMG model has been generated that harbors key genetic alterations commonly observed in human disease, and is designed to recapitulate tumor architecture, growth kinetics, and immunological features. The model incorporates oncogenic histone H3.3 K27M, mutant p53 (R167H), and PDGFRα, stably integrated into the porcine ROSA26 locus with flanking loxP sites to enable Cre-dependent oncogene activation. Transgenic animals were produced by somatic cell nuclear transfer, resulting in a litter of four DMG transgenic pigs. Current studies are focused on validating inducible oncogene expression and evaluating tumor initiation and progression in vivo.

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. We show that MALT1 is expressed in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis in macrophages, leading to enhanced macrophage migration and polarization toward an immunosuppressive (‘M2-like’) phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage anti-tumor ‘M1-like’ phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in immuno-reactivity of GBM-associated macrophages and reduced GBM tumor growth. The addition of MALT1 inhibitor to temozolomide reduces immunosuppression in the tumor microenvironment, indicating that pharmacological inhibition of MALT1 protease may enhance the efficacy of chemotherapeutic. Thus, our findings suggest that MALT1 protease inhibition represents a promising macrophage-targeted immunotherapeutic strategy for the treatment of GBM. MALT1 protease is an intracellular signalling molecule that regulates adaptive immune responses and has been implicated in the pathogenesis of hematologic and solid malignancies. Here, the authors investigate the function of MALT1 in tumor-associated macrophages. In preclinical models of glioblastoma (GBM), tumor cells induce MALT1 and NFKb signaling activation, driving macrophage polarization towards a tumor-supportive phenotype, and MALT1 inhibition enhances macrophage immunoreactivity, suppressing GBM tumor growth.

MYCN functions as a developmental oncogene, but its role in pediatric high-grade gliomas (pHGGs) remains unclear. In co-operation with Trp53 and Pten loss, MYCN initiates tumorigenesis and establishes an origin for MYCN-driven pHGGs. This transformation creates a vulnerability to PI3K and mTOR inhibition. However, prolonged treatment drives adaptive resistance through MYCN protein rebound, mediated by the attenuation of IGFBP5 and the induction of insulin-like growth factor 2. Although insulin pathway feedback has been implicated in resistance to PI3K targeted therapies, MYCN emerges as the central node of this adaptive program. Resistance can be overcame by sustained MYCN suppression using PI3K and mTOR inhibitors, combined with insulin-like growth factor 1 receptor and insulin receptor inhibitors or dietary intervention. A degradation-resistant MYCN isoform abolishes this response, establishing MYCN as both an initiating oncogene and a resistance driver and revealing a mechanistically defined therapeutic vulnerability.

Abstract Glioblastoma (GBM) continues to have limited response to immunotherapy due to an immunosuppressive tumor microenvironment that limits T cell function. Tumor-infiltrating lymphocyte (TIL) therapy has proven effective in melanoma, but in GBM, poor TIL functionality has constrained translational impact. To address these barriers, we evaluated strategies to enhance TIL efficacy through immune preconditioning, checkpoint blockade, and optimized expansion in the SB28 murine glioblastoma model, a syngeneic system engineered to recapitulate key genetic and immunologic features of human adult and pediatric high-grade glioma. SB28 tumors are generated via Sleeping Beauty transposon–mediated insertion targeting TP53, NRAS, and PDGFB pathways, resulting in tumors with low mutational burden, limited immunogenicity, and histopathologic features that more closely resemble human adult and pediatric GBM than other commonly used murine models. TILs were harvested from orthotopic SB28 tumors following neoadjuvant anti-PD-1/anti-CTLA-4 therapy and expanded ex vivo with IL-2 and CD3/CD28 stimulation. Checkpoint-exposed TILs showed enhanced in vitro tumor cell killing and elevated IFN-γ production, with sustained cytotoxicity across multiple effector-to-target ratios. In vivo, systemic anti-Thy1.2 lymphodepletion reduced peripheral CD4+ and CD8+ T cells while preserving intratumoral populations. Adoptive transfer of TILs alone produced minimal survival benefit; however, when combined with post-transfer immune checkpoint blockade, survival significantly improved in the SB28 model. Checkpoint conditioning during ex vivo expansion alone was insufficient to drive these effects, indicating the crucial role of the immune milieu encountered after TIL transfer. These results demonstrate that TIL therapy efficacy in GBM depends on both intrinsic T cell fitness and the immune context into which they are introduced, especially within immunologically “cold” tumors like SB28. Our findings support combination strategies that pair TIL therapy with immune preconditioning and checkpoint blockade to overcome resistance mechanisms in GBM and advance adoptive cellular immunotherapy for high-grade gliomas.

ABSTRACT Phototherapy, a light-activated anticancer treatment, enables localized tumor-cell killing with distinct mechanisms of action. Photoimmunotherapy (PIT) produces immunogenic tumor cell death upon near-infrared light activation of a photoabsorber through antigen-specific targeting. Photodynamic therapy (PDT) produces reactive oxygen species through red-light activation of intracellular protoporphyrin IX generated from 5-aminolevulinic acid uptake and metabolism. PIT may have limited activity in antigen-low cells, whereas PDT has less precise tumor selectivity. We combined these modalities to define their interaction, broaden cytotoxicity, and determine whether dual treatment could reduce light-dose requirements. We conjugated dinutuximab, which targets the GD2 antigen, to IRDye 700DX and characterized plasma-membrane localization by confocal and widefield microscopy. PIT and PDT monotherapies were evaluated across agent and light doses in neuroblastoma (NB) and osteosarcoma (OS) cell lines. Combination matrices were tested using interaction, highest-single-agent, and Bliss analyses. Both monotherapies demonstrated significant light-dose-dependent effects in NB and OS. PIT produced no measurable cytotoxicity in antigen-blunted control cells, whereas PDT remained effective, confirming antigen-dependence of PIT and antigen-independence of PDT. The combination interaction was significant in SK-N-BE(2) but not LM7. At selected combinations, however, dual treatment produced greater killing than the more effective matched monotherapy in both SK-N-BE(2) and LM7 (P adj ≤0.022). Notably, lowest combination of PIT 10 J/cm² plus PDT 10 J/cm 2 achieved 90.3% killing in SK-N-BE(2), exceeding higher light-dose PIT or PDT monotherapy, suggesting a light-dose sparing effect. These findings establish potent and complementary PIT-PDT activity, supporting dual phototherapy to broaden cytotoxicity and reduce light-dose requirements in GD2-expressing tumor phototherapy.

Tumor antigens are crucial for T-cell mediated immunotherapy, but identified antigens for gliomas remain limited. Aberrant splicing variants are commonly expressed in tumors, resulting in unique tumor isoforms with potential antigenic properties. Herein, we analyzed multi-omics data from 587 glioma patients and assembled a library of putative tumor-enriched isoform antigens (TIA) and corresponding peptides presented on each HLA-I allele. We constructed an individual-specific TIA peptide candidate repertoire for each patient based on their TIA expression and HLA-I haplotypes. TIAs were highly expressed, enriched with glioma malignancy, and demonstrated strong HLA-binding affinity. We focused on periostin isoform-203 (POSTN-203), which was associated with poor survival of patients and contained multiple predicted HLA-restricted peptide epitopes. A selected HLA-A11-restricted peptide from POSTN-203 (POSTN-203A11) induced antigen-specific T-cell responses against both peptide-pulsed and POSTN-203-expressing glioma cells in an HLA-specific manner. Our findings highlight TIAs as a promising source of immunogenic antigens and POSTN-203 as a potential promising target for glioma immunotherapy.

The aggressiveness of glioblastoma may be due to its limited induction of anti-tumor T cells; therefore, vaccines are attractive candidates to drive tumor-specific T cells. Heterologous prime-boost vaccination with chimpanzee adenovirus (ChAdOx1) and modified vaccinia Ankara (MVA) viral vectors can generate high tumor-targeted CD8+ T cell frequencies. Therefore, we tested whether this vaccination strategy induces effective T cell responses against murine glioblastoma. We used the orthotopic syngeneic SB28.P1A glioblastoma model expressing P1A, a mouse tumor antigen. Both prophylactic and therapeutic vaccination with ChAdOx1/MVA-P1A significantly prolonged the survival of mice with SB28.P1A tumors. Tumors were enriched for P1A-specific CD8+ T cells, with 40% of CD8+ T cells P1A-specific in the tumor-bearing hemisphere, compared to 20% in the contralateral hemisphere and 5% in the blood. Strikingly, 70% of tumor-infiltrating P1A-specific CD8+ T cells were resident memory T (Trm) cells. The adoptive transfer of sorted P1A-specific Trm cells derived from vaccinated tumor-bearing mice into the brains of naïve mice sufficiently protected mice from later challenge with tumors, while P1A-specific non-Trm cells or non-P1A-specific brain-derived CD8+ T cells did not. The capability of ChAdOx1/MVA vaccination to induce antigen-specific Trms in the brain that are sufficient to protect against glioblastoma is promising for translating this therapy into clinical trials. Supported by NIH intramural research program ZIA BC011877 and the Ludwig Institue for Cancer Research. Vaccines and Immunotherapy (VAC)

Traumatic brain injury (TBI) triggers persistent gut microbiome dysbiosis characterized by depletion of short-chain fatty acid (SCFA)-producing bacteria. However, the link between SCFA depletion and long-term neurologic impairment (LTNI) after TBI remains unclear. Previously, we and others noted the involvement of metabolite-sensing receptors and SCFA ligands in mouse models of neurodegenerative diseases, including Alzheimer’s. Here, we further investigated SCFA-mediated neuroprotection in LTNI at both microbiome and single-cell resolution using the controlled cortical impact (CCI) model of TBI with a high-yielding SCFA diet to examine their mechanistic role in pathogenesis. C57BL6/J mice were randomized to CCI (6 m/s, 2 mm) or sham surgery. Following surgery, mice were randomized to a study diet based on a balanced modification of the AIN93-G diet containing either 15

Medulloblastoma (MB) is a fast-growing and heterogeneous brain tumor arising in the cerebellum. Group 3, one of four MB subgroups (WNT, SHH, Group 3, and Group 4), is the most aggressive and malignant type in children. In this study, we identify that SMARCD3/BAF60C (SMARCD3 hereafter), a core component of the SWI/SNF chromatin-remodeling complexes, is highly expressed in Group 3 MB and Purkinje cells (PCs) of the developing cerebellum. Furthermore, elevated SMARCD3 expression is associated with patient poor outcomes, MB metastatic phenotype, and activation of the Reelin signaling pathway that is required for PC migration and positioning in cerebellar development. Conditional Smarcd3 knockout in PCs results in early death in mice, and the surviving animals exhibit significantly impaired motor coordination and balance ability. Histological staining shows disorganized PC alignment and reduced dendritic branching, confirming the critical role of the SMARCD3-Reelin pathway function in PC migration, positioning, and maturation. These all together demonstrate that the SMARCD3-associated SWI/SNF chromatin-remodeling complex regulates Reelin signaling pathway in PC migration and positioning during cerebellar development; however, this neurodevelopmental program is hijacked for MB metastatic dissemination. The study provides compelling functional evidence of SMARCD3 and the associated SWI/SNF complexes’ involvement in cerebellar development, tumor metastasis, and the molecular connections between early brain development and tumorigenesis, offering new rationales for the development of innovative therapies for patients with MB.

Abstract Background Individual-level characteristics underlying population-level variation in glioma risk and outcomes remain incompletely understood. Cancer immunosurveillance, host immunity, and some immunotherapies center on the ability of an individual’s immune cells to recognize antigen epitopes presented on MHC molecules. Inter-individual variation in HLA alleles can elicit distinct repertoires of tumor antigen for presentation to immune cells. Therefore, HLA alleles may impact glioma incidence and prognosis. Methods HLA class I (HLA-I) alleles were identified using sequencing data from four large glioma cohorts and healthy cohorts, matched on ancestry, and race- and age-matched imputed cohorts developed by the Hardy-Weinberg equilibrium were referred to determine odds ratio incidence estimated by logistic regression. HLA prognostication was quantified by Cox regression. Results We analyzed 1,215 cases of glioma patients from non-Hispanic Whites and Asians. The HLA-I allelic frequencies of gliomas generally corresponded to their distribution within each race. However, specific HLA-I alleles were significantly associated with glioma incidence and prognosis, which differ between races but were independent of age and sex. Notably, non-Hispanic White glioma patients exhibited greater HLA homozygosity rates compared with race-matched controls. HLA-C01:02 and HLA-C07:02 displayed opposing effects on glioma prognosis between races. The distinct effects were associated with their capability of presenting specific mutations that appeared at the initial or late phase of glioma progression. Conclusions Expression of specific HLA-I alleles are associated with glioma incidence and prognosis within race. HLA-I-homozygosity is a risk factor for glioma in non-Hispanic Whites. These findings may guide development of precision-guided immunotherapies for glioma.

Immunotherapy of cancer is now an essential pillar of treatment for patients with many individual tumor types. Novel immune targets and technical advances are driving a rapid exploration of new treatment strategies incorporating immune agents in cancer clinical practice. Immunotherapies perturb a complex system of interactions among genomically unstable tumor cells, diverse cells within the tumor microenvironment including the systemic adaptive and innate immune cells. The drive to develop increasingly effective immunotherapy regimens is tempered by the risk of immune-related adverse events. Evidence-based biomarkers that measure the potential for therapeutic response and/or toxicity are critical to guide optimal patient care and contextualize the results of immunotherapy clinical trials. Responding to the lack of guidance on biomarker testing in early-phase immunotherapy clinical trials, we propose a definition and listing of essential biomarkers recommended for inclusion in all such protocols. These recommendations are based on consensus provided by the Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Network (SCION) faculty with input from the SITC Pathology and Biomarker Committees and the Journal for ImmunoTherapy of Cancer readership. A consensus-based selection of essential biomarkers was conducted using a Delphi survey of SCION faculty. Regular updates to these recommendations are planned. The inaugural list of essential biomarkers includes complete blood count with differential to generate a neutrophil-to-lymphocyte ratio or systemic immune-inflammation index, serum lactate dehydrogenase and albumin, programmed death-ligand 1 immunohistochemistry, microsatellite stability assessment, and tumor mutational burden. Inclusion of these biomarkers across early-phase immunotherapy clinical trials will capture variation among trials, provide deeper insight into the novel and established therapies, and support improved patient selection and stratification for later-phase clinical trials.