bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A038: Inducing tumor associated tertiary lymphoid structures using cellular therapy
Authors: Amwas Nour , Alizadeh Darya , Brown Christine , Chiu Victor , Egelston Colt , Gumber Diana , Wang Hanmin , Williams John , Wang Leo David 
Published: February 2025

Abstract
Targeting the tumor microenvironment (TME) to be more immune permissive is a potential strategy for enhancing immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, providing a promising avenue for treating aggressive tumors such as glioblastoma multiforme (GBM). Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that arise in response to chronic inflammation and mimic the structure and function of secondary lymphoid organs. The spontaneous presence of TLS in some solid tumors, including GBM, is associated with improved clinical outcome and responsiveness to immunotherapy. I hypothesize that membrane tethered anti-LTβR Sc-Fv (mTa) T cells can function as lymphoid tissue inducer cells (LTi) and interact with lymphoid tissue organizer cells (LTo) in the TME, that express lymphotoxin-β receptor (LTβR), to nucleate TLS. To this end, we screened commercially available murine LTβR agonist antibodies to induce NFκB signaling. When a lead candidate with robust NFkB activation was injected in situ into mice orthotopically injected with a murine glioma cell line, we found multiple TLS-like lymphoid aggregates. We therefore sequenced and cloned a membrane-tethered version of this antibody alongside a CAR construct to generate mTa-CAR-T cells. mTa-CAR T cells could activate LTβR in an NFκB-GFP reporter assay. We proceeded to intratumorally inject these cells into a syngeneic mouse GBM tumor model to evaluate TLS induction and assess the ability of mTa-CAR T cells to improve antitumor efficacy and survival. This study attempts to identify strategies to remodel the TME of GBM and nucleate TLS using cellular therapy to improve the response to CAR-T therapy and survival of GBM patients.
Citation Format: Nour Amwas, Darya Alizadeh, Christine Brown, Victor Chiu, Colt Egelston, Diana Gumber, Hanmin Wang, John Williams, Leo David Wang. Inducing tumor associated tertiary lymphoid structures using cellular therapy [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A038.
Abstract A040: Novel insights into paclitaxel's role on tumor-associated macrophages in enhancing PD-1 blockade in breast cancer treatment
Authors: Kwon Minsu , Hong Jisu , Choi Seo-Won , Cho Hyojung , Lee Yoon Se 
Published: February 2025

Abstract
Background: Triple-negative breast cancer (TNBC) poses unique challenges due to its complex nature and the need for more effective treatments. Recent studies showed encouraging outcomes from combining paclitaxel (PTX) with programmed cell death protein-1 (PD-1) blockade in treating TNBC, although the exact mechanisms behind the improved results are unclear. Methods: We employed an integrated approach, analyzing spatial transcriptomics and single-cell RNA sequencing data from TNBC patients to understand why the combination of PTX and PD-1 blockade showed better response in TNBC patients. We focused on toll-like receptor 4 (TLR4), a receptor of PTX, and its role in modulating the cross-presentation signaling pathways in tumor-associated macrophages (TAMs) within the tumor microenvironment. Leveraging insights obtained from patient-derived data, we conducted in vitro experiments using immunosuppressive bone marrow-derived macrophages (iBMDMs) to validate if PTX could augment the cross-presentation and phagocytosis activities. Subsequently, we extended our study to an in vivo murine model of TNBC to ascertain the effects of PTX on the cross-presentation capabilities of TAMs and its downstream impact on CD8+ T cell-mediated immune responses. Results: Data analysis from TNBC patients revealed that the activation of TLR4 and cross-presentation signaling pathways are crucial for the antitumor efficacy of PTX. In vitro studies showed that PTX treatment enhances the cross-presentation ability of iBMDMs. In vivo experiments demonstrated that PTX activates TLR4-dependent cross-presentation in TAMs, improving CD8+ T cell-mediated antitumor responses. The efficacy of PTX in promoting antitumor immunity was elicited when combined with PD-1 blockade, suggesting a complementary interaction. Conclusions: This study reveals how PTX boosts the effectiveness of PD-1 inhibitors in treating TNBC. We found that PTX activates TLR4 signaling in TAMs. This activation enhances their ability to present antigens, thereby boosting CD8+ T cell antitumor responses. These findings not only shed light on PTX’s immunomodulatory role in TNBC but also underscore the potential of targeting TAMs’ antigen presentation capabilities in immunotherapy approaches.
Citation Format: Minsu Kwon, Jisu Hong, Seo-Won Choi, Hyojung Cho, Yoon Se Lee. Novel insights into paclitaxel's role on tumor-associated macrophages in enhancing PD-1 blockade in breast cancer treatment [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A040.
Abstract A042: Uncovering the mechanism of synergistic anti-tumor effects in FAP-CD40 + PD1-IL2v combination therapy
Authors: Nguyen Thuy Trinh , Kunz Leo , Grazina de Matos Ines , Trumpfheller Christine , Umaña Pablo 
Published: February 2025

Abstract
Therapies targeting the activation and recruitment of immune cells such as T cells or DCs to the tumor microenvironment (TME) are considered as highly promising approaches to improve anti-tumor responses. Here, we evaluated the synergistic efficacy of PD1-IL2v in combination with FAP-CD40 in the syngeneic and notoriously difficult to treat KPC-4662 tumor model. PD1-IL2v drives the expansion of stem-like CD8 T cells and their differentiation into effector CD8 T cells, while FAP-CD40, a tumor targeted CD40 agonist antibody, triggers the activation of DCs. Our aim was to uncover spatial patterns of immune cell organization within the tumor tissue potentially being responsible for this synergistic activity of this combination treatment. To assess how the combination treatment influences the spatial organization of immune cells within the TME, we employed 3D immune phenotyping (3DIP). 3DIP combines multiplexed confocal imaging with a quantitative analysis pipeline, enabling the visualization and quantification of up to 12 markers in 70 μm thick tumor sections and thus the detailed characterization of complex cellular subsets and intercellular interactions within intact tumor tissues. Mice bearing subcutaneous, fibrotic and immune excluded KPC tumors were treated with FAP-CD40 and PD1-IL2v, either as monotherapies or in combination. PD1-IL2v or FAP-CD40 monotherapy resulted in delayed tumor growth compared to the vehicle. Significant tumor regression was observed only when PD1-IL2v was combined with FAP-CD40. Interestingly, 3DIP analysis of treated tumor tissues revealed strong infiltration of both CD4 and CD8 T cells in general. Only quantitative spatial analysis of tumor tissues revealed the presence of dense clusters of CD4 and CD8 T cells, co-localizing with dendritic but not B cells, throughout tumor tissues and only after combination treatment, underlining the importance of evaluating spatial organization when studying immune-modulating therapies. Taken together, these findings suggest that the observed efficacy upon combination of PD1-IL2v with FAP-CD40 is driven by the increased proliferation, recruitment and organization of CD4 and CD8 T cells in the tumor tissue. This could be mediated by dendritic cells activated by FAP-CD40, which may also play a role in reprogramming exhausted T cells into effector T cells within the intratumoral immune clusters, ultimately leading to tumor regression.
Citation Format: Thuy Trinh Nguyen, Leo Kunz, Ines Grazina de Matos, Christine Trumpfheller, Pablo Umaña. Uncovering the mechanism of synergistic anti-tumor effects in FAP-CD40 + PD1-IL2v combination therapy [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A042.
Abstract A047: Harnessing localized anti-cancer treatments for systemic anti-metastatic tumor responses in aged mice through the combination of local anti-CD40 agonist and cGAMP/irradiation
Authors: Yan Minglu , Chen Zhijian "james" 
Published: February 2025

Abstract
Immune checkpoint inhibitors and systemic chemotherapy have limited efficacy in metastatic cancers, particularly in elderly patients, and are associated with significant toxicity. Localized therapies, such as irradiation and STING agonists, have the potential to elicit systemic anti-tumor immune responses but remain clinically suboptimal. Strategies to fully leverage the systemic benefits of localized treatments are yet to be established. Here, we show that local delivery of anti-CD40 agonist, in combination with irradiation or cGAMP, effectively eradicates distant metastatic tumors in young and aged mice, an effect unattainable with single-agent therapies. Irradiation and cGAMP enhance antigen-presenting cell activation and NK cell infiltration, driving regression of primary tumors, while CD40 stimulation promotes DC1 migration to tumor-draining lymph nodes, priming tumor-specific T cells by suppressing FoxP3+ regulatory CD4+ T cells and expanding T-bet-expressing CD4+ and CD8+ T cells. Notably, the combination of anti-CD40 and STING agonists reprograms the myeloid compartment into a distinct pro-inflammatory state, marked by high Ly-6C expression and increased production of IL-12, type I/II interferons, and GM-CSF. This reprogramming further promotes the induction of CD4+CD8+ double-positive cytotoxic T cells and NK cell infiltration, ultimately driving robust tumor rejection. These findings present a novel localized therapeutic strategy that synergizes with current immunotherapies and offers promising advancements in cancer treatment.
Citation Format: Minglu Yan, Zhijian "james" Chen. Harnessing localized anti-cancer treatments for systemic anti-metastatic tumor responses in aged mice through the combination of local anti-CD40 agonist and cGAMP/irradiation [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A047.
Abstract A059: IL-27 elicits a cytotoxic CD8+ T cell program to enforce tumour control
Authors: Breart Beatrice , West Nathaniel 
Published: February 2025

Abstract
Cytotoxic CD8+ T lymphocytes (CTL) are essential for anti-tumour immunity but are frequently dysfunctional in established tumours. Cytokines that sustain CTL activity are attractive for cancer immunotherapy, but avoiding systemic inflammatory toxicity remains a challenge for their clinical use. Here, we show that expression of a CTL signature is strongly associated with IL-27 expression in human and murine tumours. In mice, IL-27 acts directly on tumour-specific CTL to promote their persistence and effector function in the tumour microenvironment (TME). Moreover, treatment with inducible IL-27 overexpression or a half-life-extended IL-27 protein in vivo is well tolerated, induces regression of established tumours, drives an enhanced cytotoxic program in anti-tumour CTL, and synergizes with PD-L1 blockade. In cancer patients treated with anti-PD-1/PD-L1[bb1] therapy, high expression of IL-27 correlates with improved clinical response, and IL-27 supports human CTL function during chronic antigen stimulation. Our data demonstrate that endogenous IL-27 is essential for anti-tumour immunity and that IL-27 receptor agonism can safely improve anti-tumour T cell responses alone or in combination with PD-L1 blockade.
Citation Format: Beatrice Breart, Nathaniel West. IL-27 elicits a cytotoxic CD8+ T cell program to enforce tumour control [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A059.
Abstract A061: Discovery of resilient T cells from patients in responses to combination immunotherapy and their metabolic features
Authors: Dong Haidong , Gicobi Joanina K 
Published: February 2025

Abstract
Salvage combination therapy including radiotherapy and immunotherapy has been used to reduce tumor burden and tumor-related symptoms in patients with advanced cancer that is refractory to ICI monotherapy. Among those patients who experienced significant tumor regression in responses to combination therapy, we identified a rebound of effector CD8+ T cells with high cytotoxic capacity and metabolic fitness. We use the term T cell resilience to explain the rebound of cytotoxic CD8+ T cells in response to combination therapy and examine the underlying mechanisms of T cell resilience. Resilient T cells are enriched in CX3CR1+ CD8+ T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). We found ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8+ T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. Importantly, ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers and improve the efficacy of tumor-infiltrating lymphocytes (TIL) therapy in animal models. Our results demonstrate the presence of resilient T cells in patients, suggest that T cell resiliency is attributed to their metabolic reprogram mediated by ME1, which is a new T cell-intrinsic therapeutic target for T cell-based immunotherapy.
Citation Format: Haidong Dong, Joanina K Gicobi. Discovery of resilient T cells from patients in responses to combination immunotherapy and their metabolic features [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A061.
Abstract A065: Innovative Epigenetic Techniques for Early Leukemia Detection: Advances in Laboratory Diagnostics
Authors: Gameel Fathelrahman 
Published: February 2025

Abstract
Background: Leukemia is a group of hematological malignancies characterized by the abnormal proliferation of blood cells. The epigenetic regulation of gene expression has emerged as a key factor in leukemia development and progression. This study aims to investigate the epigenetic landscape in a cohort of Sudanese leukemia patients, exploring potential biomarkers for diagnosis and therapeutic intervention. Methods: A cross-sectional experimental study was conducted on 200 confirmed leukemia patients from various hospitals in Sudan. Comprehensive clinical data, including demographic information, leukemia subtypes, and treatment history, were collected. Blood samples were obtained from each patient, and DNA was extracted for epigenetic analysis, focusing on DNA methylation patterns and histone modifications. Advanced molecular techniques, including bisulfite sequencing and chromatin immunoprecipitation (ChIP), were employed to identify key epigenetic changes associated with leukemia in the Sudanese population. Results: Preliminary findings revealed distinct epigenetic signatures associated with different leukemia subtypes, particularly in genes related to cell cycle regulation and apoptosis. Several differentially methylated regions (DMRs) were identified as potential biomarkers for early detection and treatment response monitoring. Additionally, specific histone modifications correlated with disease severity and prognosis. Conclusion: This study highlights the significance of epigenetic alterations in Sudanese leukemia patients and underscores their potential as diagnostic and prognostic tools. Further research is needed to validate these findings and explore the therapeutic implications of targeting epigenetic changes in leukemia.
Citation Format: Fathelrahman Gameel. Innovative Epigenetic Techniques for Early Leukemia Detection: Advances in Laboratory Diagnostics [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A065.
Abstract A067: PRMT7 deficiency in T cells enhances immune response and fosters an anti-tumor microenvironment in melanoma
Authors: Srour Nivine , Xiong Yan , Yu Zhenbao , Papadopoulos Theodore , Luo Kaixiu , Santinon François , Barsyte-Lovejoy Dalia , Victoria delRincon Sonia , Jian Jin , Richard Stéphane 
Published: February 2025

Abstract
Exploration in the field of epigenetics has unveiled the significance of protein arginine methyltransferases (PRMTs) in normal development and disease. Our research identified PRMT7 as a promising target for enhancing the efficacy of cancer immunotherapy in melanoma (Srour et al., 2022, Cell Reports 38(13):110582). To investigate if PRMT7 plays a role in the tumor microenvironment especially in tumor infiltrating lymphocytes (TILs), we bred PRMT7FL/FL mice with CD4-Cre mice (CKO) to generate PRMT7 deficient T cells. PRMT7 CKO mice exhibited a substantial increase in peripheral CD8+ but not CD4+ T cells. These CD8+ T cells had an enhanced T cell effector memory-like phenotype as assessed by CD44, CD62L expression. Interestingly, PRMT7 CKO mice exhibited reduced melanoma growth following subcutaneous injection of B16.F10 cells. Ex vivo stimulation of PRMT7 CKO CD8+ T cells with αCD3 and αCD28 resulted in enhanced proliferation compared to control CD8+ T cells. To replicate PRMT7 depletion observed in the CKO model, we developed novel VHL-ligand coupled PROTAC inhibitors targeting PRMT7. Notably, PRMT7-deficient CD8+ T cells, whether derived from CKO mice or wild-type mice treated with PRMT7 PROTACs, exhibited enhanced cytotoxic activity against melanoma cells in vitro. Furthermore, our data show that adoptive cell transfer (ACT) with PRMT7-deficient OT-I T cells improves tumor control, while ACT with wild-type OT-I effectors has a smaller effect. Transcriptomic analysis of PRMT7-deficient CD8+ T cells revealed multiple alternative splicing defects, along with upregulation of genes related to the NF-κB pathway. Our findings highlight a crucial role for PRMT7 in regulating CD8+ T cell function, reinforcing the need to therapeutically target PRMT7 for adoptive T cell immunotherapies and CAR T cell treatments.
Citation Format: Nivine Srour, Yan Xiong, Zhenbao Yu, Theodore Papadopoulos, Kaixiu Luo, François Santinon, Dalia Barsyte-Lovejoy, Sonia Victoria delRincon, Jin Jian, Stéphane Richard. PRMT7 deficiency in T cells enhances immune response and fosters an anti-tumor microenvironment in melanoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A067.
Abstract A069: Combined PD-L1 expression in malignant and infiltrating cells predicts survival in hepatocellular carcinoma with atezolizumab and bevacizumab
Authors: Kim Min gu , Sung Pil soo , Jang Eun ji 
Published: February 2025

Abstract
Background: PD-L1 expression is abundant not only in malignant cells but also in infiltrating cells within the tumor microenvironment (TME) of hepatocellular carcinoma (HCC). This study explored the association between PD-L1 expression in TME and outcomes in HCC patients treated with atezolizumab plus bevacizumab (AB), emphasizing the implications of PD-L1 expression in both malignant and tumor-infiltrating cells. Methods: This study included 72 patients with HCC who underwent percutaneous core needle liver biopsy before AB treatment between September 2020 and December 2023. PD-L1 expression on tumor tissues was assessed using the combined positive score (CPS) with cutoff values of 1 and 10, utilizing antibody clone 22C3 (Dako). Results: The distribution of PD-L1 CPS included 24 patients with CPS&lt;1, 33 patients with CPS 1–10, and 15 patients with CPS ≥10. Significant differences in OS were observed across the three groups, with CPS ≥10 showing the highest survival rates (p = 0.010). Patients with CPS ≥10 had better OS than those with CPS&lt;10 (mOS 14.8 vs. 8.3 months, P = 0.046), and CPS ≥1 had better OS than CPS&lt;1 (P = 0.021). For PFS, the CPS ≥10 group had the highest mPFS of 11.0 months among the three groups (P = 0.044). Objective response rates (ORR) were higher in the PD-L1 CPS ≥10 group than in the 1-10 and &lt;1 group (53.3%, 27.3%, and 16.7%, respectively; P = .047). Multivariate analysis identified that PD-L1 expression ≥10 and ≥1 were associated with favorable outcomes regarding OS (hazard ratio [HR] 0.283, P = .027 and HR 0.303, P = .006, respectively). Conclusions: Combined PD-L1 expression in malignant and tumor-infiltrating cells can be a promising biomarker for the prognosis of HCC patients treated with AB.
Citation Format: Min gu Kim, Pil soo Sung, Eun ji Jang. Combined PD-L1 expression in malignant and infiltrating cells predicts survival in hepatocellular carcinoma with atezolizumab and bevacizumab [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A069.