Citations

Abstract Although CD8+ T cells face intense immunosuppressive and metabolic pressures within the tumor microenvironment (TME), a subset of these cells can mount resilient responses to immune checkpoint inhibitor (ICI) therapy. We recently identified a population of such resilient CD8+ T cells in patients with advanced solid tumors who were unresponsive to standard-of-care cancer therapies but showed clinical benefit from ICI or combination ICI therapy. Among these resilient CD8+ T cells, which retain their cytotoxic capacity to eliminate tumor cells, we observed upregulation of ME1 and downregulation of DUSP2 in responders to the combination therapy. However, the mechanistic role of altered ME1 and DUSP2 expression in shaping resilient CD8+ T cell responses in cancer remains to be fully elucidated. To that end, we used scRNA-seq, bulk RNA-seq, and ATAC-seq analyses to investigate how altered expression of DUSP2 and ME1 regulates transcription of genes encoding effector molecules in both human and mouse CD8+ T cells. Additionally, we utilized CD8+ T cell-specific DUSP2 knockout (KO) and ME1 transgenic (Tg) mouse models to define the roles of these genes in effector T cell differentiation and antitumor responses in vivo. We found that DUSP2 downregulation enhances the expression of effector molecules (e.g., GZMB and NKG7) in CD8+ T cells, accompanied by increased cytotoxic activity. Mechanistically, reduced DUSP2 expression promotes chromatin accessibility at effector gene loci by modulating the nuclear residency balance between BAF and NuRD, two chromatin remodeling complexes with opposing functions. In parallel, ME1 overexpression enables activated CD8+ T cells to bypass the classical glycolysis pathway in favor of the pentose phosphate pathway (PPP), thereby boosting ATP production while minimizing excess ROS accumulation and increasing effector molecule expression via an epigenetic mechanism. Our study reveals a previously unknown adaptive mechanism by which resilient CD8+ T cells maintain their cytotoxic function within the TME. This is achieved through integrated reprogramming of epigenetic regulation and metabolic fitness, enabling compensation for metabolic stress in the TME and restoration of responsiveness to ICI-based combination therapy, even in patients with substantial tumor burden. Citation Format: Haidong Dong. Epigenetic and metabolic reprogramming for resilient CD8+ T cell responses in the tumor microenvironment [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A001.

Abstract Neuroblastoma (NB) accounts for approximately 10% of pediatric cancer-related deaths. High-risk NB is often metastatic at diagnosis with a poor 5-year survival rate (<50%) despite intensive multimodal therapy. GD2, a disialoganglioside glycolipid expressed in nearly all NBs, is a well-validated immunotherapy target. Although GD2-CAR-T cells have been clinically evaluated, their efficacy remains limited due to poor tumor infiltration and the immunosuppressive tumor microenvironment (TME), underscoring the need for alternative immune-based approaches. Given the inherent capacity of macrophages to infiltrate solid tumors, phagocytose cancer cells, and modulate the TME, we engineered the GD2-CAR macrophage (GD2-CAR-M) as a novel therapeutic platform for NB. GD2-specific CAR constructs containing the Hu3F8 single-chain variable fragment (scFv) were designed, validated, and introduced into multiple human and murine monocyte/macrophage cell lines via lentiviral transduction. Fluorescence microscopy and flow cytometry demonstrated a significant enhancement in the phagocytosis of GD2-high NB cells and the phagocytic efficiency correlating positively with GD2 expression levels, suggesting antigen-specific phagocytosis by GD2-CAR-M. Our further in vivo studies using an immunocompetent MYCN-driven NB non-genetically engineered mouse model (MYCN-NGEMM) showed that treatment with GD2-CAR-M markedly reduced tumor burden and prolonged survival compared with controls. Notably, mice bearing GD2-high-tumors exhibited significantly improved survival, including one complete remission among ten treated animals. Histological analyses revealed increased connective tissue deposition and decreased tumor cell density, suggesting TME remodeling. Single-cell RNA sequencing and immunohistochemistry further demonstrated enhanced infiltration of macrophages, neutrophils, and T cells, indicating a shift from a “cold” to a “hot” immune TME following GD2-CAR-M treatment. Consistent antitumor effects were also observed in our dbh-MYCN transgenic zebrafish with spontaneous development of NB following GD2-CAR-M administration. Taken together, GD2-CAR-M exhibits potent antigen-specific antitumor activity and promotes favorable TME remodeling in NB models. These findings highlight GD2-CAR-M as a promising translational immunotherapy strategy for high-risk NB. Citation Format: Shizhen (Jane) Zhu, Ke-En Tan, Kok Siong Yeo, Cheng Zhang, Caleb T. Baker, Alexis M. Sosic, Eddie Lim . Yat Yuen, Choong Yong Ung, Stephanie F. Polites, Yi Lin, William A. Weiss, Hu Li. Harnessing GD2-CAR macrophages to target high-risk neuroblastoma [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B005.

Abstract Endometriosis (EMS) is an estrogen-dependent, chronic inflammatory disease in which endometrial-like tissue grows outside the uterus, leading to pelvic pain, dysmenorrhea, dyspareunia, and infertility. Increasing evidence shows that these symptoms do not arise from the presence of ectopic tissue alone. Rather, they reflect a sustained neuroimmune process in which inflammatory, neural, and stromal pathways continuously interact. Within the peritoneal cavity of EMS, immune activation elevates cytokines such as IL-1β, IL-6, and TNF-α, which stimulate production of neurotrophic mediators including NGF, BDNF, and IGF-1. These signals induce sensory-nerve sprouting, lower nociceptor thresholds, and convert lesions into hyperinnervated, pain-generating structures. Once these fibers infiltrate lesions, they release neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP). Rather than simply transmitting nociceptive signals, these neurons actively reshape the lesion microenvironment. SP and CGRP amplify inflammation, promote immune-cell recruitment, and drive epithelial–mesenchymal transition and myofibroblast differentiation, accelerating the fibrotic remodeling characteristic of deep infiltrating endometriosis. This neuropeptide-driven activity strengthens the lesion’s neuroimmune profile and forms a feed-forward loop in which inflammation, nerve growth, and fibrosis reinforce one another over time. Persistent nociceptive input from sensitized lesions produces downstream changes in the central nervous system. Within the spinal cord, activated microglia and astrocytes release proinflammatory mediators that enhance excitatory signaling and diminish inhibitory tone. With continued input, spinal and cortical circuits undergo neuroplastic changes that give rise to central sensitization, hyperalgesia, allodynia, and the cross-organ sensitization that links pain across the uterus, bladder, bowel, and pelvic floor. These long-range effects explain why pain may persist even when visible lesions are small or surgically removed. Together, these findings position endometriosis as a chronic systemic neuroimmune disorder maintained by reciprocal signaling between immune cells, sensory neurons, and central pain networks. Viewing EMS through this lens highlights multiple therapeutic entry points. Targeting NGF–TrkA and CGRP–RAMP1 signaling, modulating macrophage and B-cell function, dampening glial activation, or applying neuromodulatory techniques offers a more rational pathway to interrupt the self-reinforcing neuroimmune loop that sustains pain. Integrating immunologic and neurobiologic evidence therefore provides a foundation for mechanism-based therapies capable of delivering more durable relief and improving long-term quality of life. Citation Format: Ariana F. Rahman. Endometriosis as a Neuroimmune Disorder: Integrating Inflammation, Innervation, and Sensitization [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A062.

BACKGROUND AND OBJECTIVES: Ventriculoperitoneal shunt (VPS) placement is a common treatment for idiopathic normal pressure hydrocephalus (iNPH), but patients may require VPS revision. This study aims to evaluate the effectiveness of a standardized VPS placement protocol by comparing indications and rates of shunt revision compared with a historical institutional cohort. METHODS: All patients treated with VPS for “suspected” iNPH at a tertiary care center between January 2000 and January 2023 were retrospectively reviewed and divided into temporally distinct historical (before 2017) and standardized (after 2017) cohorts. Cumulative incidence and timing of VPS revision were compared using competing risks analyses. RESULTS: A total of 561 patients (median age 75.0 years) were identified with 324 (57.8%) in the historical and 237 (42.2%) in the standardized cohorts. Significant variations in surgical technique and shunt hardware were noted between the cohorts. With a median follow-up of 11.4 months for historical and 12.4 months for standardized cohort, shunt revisions occurred in 19.4% and 8.4% of patients in the historical and standardized cohorts, respectively ( P < .001). Revision indications also varied significantly with lower rates of overdrainage ( P < .001), infection ( P < .001), and proximal malfunction ( P = .042) but higher rate of distal malfunction ( P = .03) in the standardized cohort. Notably, no infections were noted in the standardized cohort. CONCLUSION: Risk of shunt revision among iNPH patients may be associated with modifiable factors related to surgical technique and shunt hardware selection. Importantly, no short-term complications such as hemorrhage, infection, or catheter malposition were observed with the standardized protocol. Development and refinement of standardized shunt protocols for iNPH patients should be commonplace to facilitate tracking, identification, and modification of modifiable technical risk factors.

BACKGROUND AND OBJECTIVES: The purpose of this study was to analyze the impact of patient-specific rods on mechanical complications after adult thoracolumbar spinal deformity surgery. METHODS: A consecutive series was analyzed of 200 adult thoracolumbar spinal deformity patients. Half of the patients (n = 100) had surgery just before implementing patient-specific rods, and the other 100 patients had surgery immediately after adoption of patient-specific rods. All patients had instrumented fusions from the thoracic spine to the pelvis. Mechanical complications were defined as rod fracture, proximal junctional kyphosis, proximal junctional failure (revision surgery requiring proximal fusion extension), and/or revision surgery for rod fracture or pseudoarthrosis. Minimum follow-up was 2 years. RESULTS: A total of 200 patients were included with a median (IQR) age of 68 (61, 73), body mass index of 28 (25, 32), and 73% were female. The patients with patient-specific rods compared with those without had less preoperative kyphosis (39° vs 44°, P = .01), a higher median number of rods (4 vs 2, P = .04), more often a combined anterior-posterior approach (61% vs 46%, P = .047), more commonly a upper instrumented vertebra vertebroplasty (67% vs 45% P = .003), and postoperatively had less thoracic kyphosis (45% vs 49%, P = .02). Patient-specific rod patients had a lower rate of mechanical complications (29% vs 47%, P = .01), a lower rate of rod fracture (3% vs 16%, P = .003), and shorter operative times (215 minutes vs 250 minutes, P = .04). On multivariable analysis, the only 2 independent predictors of reducing the rate of mechanical complications were the utilization of patient-specific rods (odds ratio 0.47, P = .013, CI 0.26-0.85) and lower postoperative thoracic kyphosis (odds ratio 1.02, P = .04, CI 1.00-1.05). CONCLUSION: In a consecutive series of adult thoracolumbar spinal deformity patients, patient-specific rods reduced the odds of mechanical complications by over 50%. Adoption of patient-specific rods should be considered to optimize patient outcomes after adult spinal deformity surgery.