bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B031: CD27-independent tonic immune checkpoint CD70 signaling provides anti-cancer drug resistance to malignant B cell lymphoma
Authors: Kim Jaemin , Lee Jaewoong
Published: February 2025

CD70 and its ligand CD27 are immune checkpoint molecules that are abnormally expressed in various hematological malignancies. Simultaneous expression of CD70 and CD27 in cancer cells promotes stemness, proliferation, and survival of these malignancies. Moreover, CD70 in cancer cells binds to CD27 in Treg, leading to survival of Treg, which contributes to immune evasion within the tumor microenvironment. We found that the expression of CD70, but not CD27, is induced upon engagement of B cell receptor (BCR). Malignant B cells that harbor constitutively active BCR signaling, therefore, highly expressed CD70 with no correlation of CD27 expression. Interestingly, we found CD70 was a CD27-independent biomarker predicting poor clinical outcomes in diffuse large B-cell lymphoma (DLBCL). To analyze how CD70 independently contributes to malignancy in DLBCL, we generated CD70-deficient DLBCL cells using non-viral CRISPR electroporation. Surprisingly, CD70-deficient lymphoma cells exhibit downregulation of BCL2 family expression, increased apoptosis, and increased sensitivity to vincristine, doxorubicin, and cyclophosphamide. These results indicate that CD70 contributes to chemotherapy resistance independently of CD27. To target the high expression of CD70 that contributes to chemotherapy resistance, we analyzed public Chip-seq data. This analysis revealed that STAT3 acts as a transcription factor for CD70. Consistently, CRISPR-mediated deletion of STAT3 in lymphoma cells dramatically downregulated surface expression of CD70 in parallel with increased anti-cancer drug sensitivity. Therefore, Ruxolitinib, a JAK1/2 kinase inhibitor, leads to decreased CD70 expression by disrupting the JAK-STAT3 signaling pathway, further overcomes chemotherapeutic drug resistance. Ultimately, to effectively eliminate cd70-high malignant b cells that are resistant to conventional chemotherapy, we developed a bike (bispecific nk cell engager) targeting both CD70 and CD16, and testing its immuno therapeutic efficacy.

Citation Format: Jaemin Kim, Jaewoong Lee. CD27-independent tonic immune checkpoint CD70 signaling provides anti-cancer drug resistance to malignant B cell lymphoma [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 B031.
Abstract B040: Transcriptomic meta-analysis identifies robust, tissue-agnostic gene expression signature of immune checkpoint blockade response
Authors: Guo Yu Amanda , Tan Aaron , Kulshrestha Tanmay , Chang Mei Mei , Lau Dawn , Wang Lan Ying , Tay Timothy , Kassam Irfahan , Revkov Egor , Rizzetto Simone , Tan Iain , Tan Daniel , Skanderup Anders
Published: February 2025

Immune-checkpoint therapy (ICB) has conferred significant and durable clinical benefit to some cancer patients. However, most patients do not respond to ICB, and reliable biomarkers of ICB response are needed to improve patient stratification. Here, we performed a transcriptome-wide meta-analysis across 1,486 tumors of 5 cancer types from ICB-treated patients and tumors with expected ICB outcomes based on microsatellite status. Using a robust transcriptome deconvolution approach, we inferred cancer and stroma-specific gene expression differences and identified cell-type specific features of ICB response across cancer types. Our analysis revealed a lack of cancer-cell intrinsic gene expression signatures associated with ICB response across tumor types. Strikingly, PD-L1 expression in stromal cells, but not cancer cells, is correlated with ICB response across cancer types. In stromal cells, we identified multiple immunomodulators and checkpoint genes associated with ICB response across cohorts and tumor types. Many of these genes, such as CXCL9, CXCL13, and IFNG, have previously been linked with ICB response. In addition, we uncovered a subset of novel and potentially immune-suppressive genes, including FCER1A, that negatively correlated with response. Using these conserved stromal-specific gene signatures, we developed a multivariate classifier of ICB response that demonstrated improved accuracy over existing biomarkers in unseen patient cohorts and tumor types, including a cohort of 50 newly sequenced late stage lung cancer patients treated with ICB. In summary, our unbiased transcriptome-wide analysis failed to identify cancer-cell intrinsic expression signatures of ICB response conserved across tumor types, suggesting that cancer cells lack tissue-agnostic transcriptomic features of ICB response. Our results challenge the prevailing dogma that cancer cells present tissue-agnostic molecular markers that modulate immune activity and ICB response, which has implications on the development of improved ICB diagnostics and treatments.

Citation Format: Yu Amanda Guo, Aaron Tan, Tanmay Kulshrestha, Mei Mei Chang, Dawn Lau, Lan Ying Wang, Timothy Tay, Irfahan Kassam, Egor Revkov, Simone Rizzetto, Iain Tan, Daniel Tan, Anders Skanderup. Transcriptomic meta-analysis identifies robust, tissue-agnostic gene expression signature of immune checkpoint blockade response [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 B040.
Abstract B045: Siglec receptors suppress T cell immunity via trogocytosis and represent degradable targets for cancer immunotherapy
Authors: Wang Chao
Published: February 2025

Cancer therapy has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, particularly those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. To overcome therapeutic resistance, identifying and targeting new types of checkpoints, such as glycan-binding immune checkpoints, may offer a promising strategy to reprogram the TME by suppressing tumor-promoting factors. Sialic acid-binding immunoglobulin-like lectin (Siglec) receptors, especially the inhibitory members constitutively expressed on myeloid cells, play an immunosuppressive role in innate immunity. Here, we identify Siglec-7 and -9 immunosuppressors as novel glyco-immune checkpoints that inhibit T cell function and anti-tumor immunity. We discovered that T cells in the TME acquire these Siglec checkpoints from myeloid cells via trogocytosis, impairing T cell activity by dephosphorylating T cell receptor (TCR)-related signaling pathways through engagement with tumor-associated sialoglycans. Using sulfur(VI) fluoride exchange (SuFEx) click chemistry, we developed a high-affinity ligand specific for Siglec-7 and -9, and converted it into a degrader for targeted lysosomal degradation of both Siglecs. This degrader efficiently reduced Siglec levels in T cells and myeloid cells, significantly restoring T cell function and enhancing anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, reshaped the TME and generated durable T cell memory, resulting in excellent tumor control in multiple murine models. These findings underscore the significance of degrading exogenously acquired Siglec checkpoints on T cells as a novel strategy to overcome resistance to established checkpoint inhibitors in cancer immunotherapy.

Citation Format: Chao Wang. Siglec receptors suppress T cell immunity via trogocytosis and represent degradable targets for cancer immunotherapy [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 B045.
Abstract B047: Stromal senescence and response to immune checkpoint inhibition in melanoma
Authors: Sojo Giselle Burton , Schmidt Marcel O
Published: February 2025

Melanoma is the 8th most commonly diagnosed cancer in the United States, predominantly driven by exposure to UV radiation leading to an abundant oncogenic mutational burden. However, very few models incorporate these mechanisms in their representation of the disease significantly influencing treatment responses. To address this, our lab uses the Yale University Melanoma Model (YUMM) irradiated cell line that contains clinically represented mutations that are imperative to melanoma development. As a result, these cells are sensitive to combination immune checkpoint inhibition making them a superior system to study the immune response in melanoma over less representative lines such as B16. These cells are injected into a syngeneic in vivo murine system C57/Bl6 INK-ATTAC mice with a senescent cell depletion cassette exclusively expressed in the host stroma, incorporating cellular senescence as a key contributor to the host response to cancer. This dual system allows for the exploration of the immune response that patients experience after receiving ICI treatment in concert with senescent stromal cell burden in the tumor microenvironment (TME). INK-ATTAC mice bearing single cell clone YUMM tumors are treated with a combination of immune checkpoint inhibitors (aPD-1+aCTLA-4) to generate both responder and non-responder phenotypes. Upon clearance of senescent cells from the TME via injection of AP20187, the proportions of these response phenotypes shift in both pro- and anti-tumor directions. Immunohistochemical analyses show a significant negative correlation of immune infiltration with tumor size, where T cells show a 2-fold increase as tumor size is reduced as a result of ICI and AP+ICI treatment. More in-depth analysis of tumor infiltrating lymphocytes and myeloid cells through Cytometry Time of Flight (CyTOF) of a specific single cell clone reveal that the proportions of immunosuppressive myeloid cells to cytotoxic T cells are key drivers of response phenotypes in AP+ICI treated tumors. Our findings suggest that stromal cellular senescence potentially have pro- and anti-tumor effects, thus influencing both treatment efficacy and resistance mechanisms that prevent response to immune checkpoint inhibition.

Citation Format: Giselle Burton Sojo, Marcel O Schmidt. Stromal senescence and response to immune checkpoint inhibition 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 B047.
Abstract B067: An antigen-specific t cell stimulation and expansion platform for immunological investigation of the Ad5.F35-GUCY2C-PADRE vaccine in gastrointestinal cancers
Authors: Sun Zhengyang , Singh Jagmohan , Cao Miao , Glowacki Anne , Zhan Tingting , Bashir Babar , Waldman Scott A , Snook Adam E
Published: February 2025

Background: Collectively, cancers of the esophagus, stomach, pancreas, and colorectum (“GI cancers”) are the leading cause of cancer-related death. Despite standard of care, 30-90% of GI cancer patients experience tumor recurrence. In colorectal cancer (CRC), guanylyl cyclase C (GUCY2C), a transmembrane heat-stable enterotoxin receptor, is overexpressed in more than 95% of colorectal tumors and in subsets of gastroesophageal and pancreatic tumors. We are conducting a Phase 2A, dose-finding, single-center, open-label, randomized trial (NCT04111172) to evaluate the safety and immunogenic activity of three dose levels of the Ad5.F35-GUCY2C-PADRE vaccine in adult patients with select solid tumors (colorectal, pancreatic, or gastroesophageal) who are at high risk of relapse following definitive surgery and adjuvant therapy. To further investigate the immunogenicity of the GUCY2C-targeting vaccine across diverse patient populations and facilitate downstream laboratory-based studies—such as autologous T cell expansion, TCR sequencing and cloning, and in vivo patient-derived xenograft (PDX) models—we explored the feasibility of a protocol for the stimulation and expansion of antigen-specific T cells derived from peripheral blood mononuclear cells (PBMCs). Methods: PBMCs from healthy donors were used as a pilot to optimize this protocol and assess its efficacy. PBMCs were cultured in vitro for approximately 10 days with adjuvants, cytokine cocktails, and antigen-specific peptides. The enriched T-cell populations were then evaluated for antigen-specific targeting using flow cytometry and ELISPOT analysis. Results and Conclusion: The stimulation protocol successfully expanded both CD4+ and CD8+ effector T cells. The final T cell population was predominantly CD8+ T cells, which secreted IFNγ following CEF (CMV, EBV, Influenza), but not MOG (self-antigen myelin oligodendrocyte glycoprotein) peptide stimulation, indicating antigen-specific reactivity of the expanded T cells. Further studies, including cytotoxicity assays and antigen-presenting cell (APC)-based longitudinal expansion, are necessary to support the high-throughput application of this protocol for future preclinical and clinical investigations.

Citation Format: Zhengyang Sun, Jagmohan Singh, Miao Cao, Anne Glowacki, Tingting Zhan, Babar Bashir, Scott A Waldman, Adam E Snook. An antigen-specific t cell stimulation and expansion platform for immunological investigation of the Ad5.F35-GUCY2C-PADRE vaccine in gastrointestinal cancers [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 B067.
Abstract B072: Circulating tumor DNA as a prognostic, diagnostic, and clinical assessment tool for evaluation and management of Ewing's sarcoma: a systematic review
Authors: Yerigeri Keval
Published: February 2025

Introduction: Circulating tumor DNA (ctDNA) can be analyzed noninvasively to obtain valuable information for genetic profiling, prognostication, and disease progression/ response to treatment. Use of ctDNA is not routine for Ewing’s sarcoma (EWS), but well-known driver mutations (e.g., EWSR1-FLI1, EWS-ERG) makes for straightforward identification by genomic sequencing or PCR techniques. We review the current literature on applications of ctDNA for EWS. Methods: The PubMed database was queried for all articles on Ewing sarcoma and circulating tumor DNA; 81 hits were identified per the search strategy. Articles were then screened by the eligibility criteria: (1) human patients with definitive, histopathological EWS, (2) analysis of ctDNA (not RNA) from peripheral blood specimens (e.g., serum, plasma), (3) articles are original; not reviews, editorials, or duplicates. N=32 articles met all criteria. Results: 7 studies were case reports or series with single EWS cases. 3 studies specifically used ctDNA to assess for stem cell contamination prior to harvesting; ctDNA was used to associate tumor cell contamination with increased risk of recurrence (including in non-metastatic primary disease per one study). 2 studies use ctDNA to trend disease response to treatments (10 patients each). Of the remainder, 3 studies used whole genome sequencing (116 patients total), 2 used next generation sequencing (86 patients), 6 used digital droplet PCR (168 patients), 4 used real-time PCR (115 patients), and 1 used multiplex PCR (3 patients). Conclusion: This review provides comprehensive evidence for the utility of ctDNA in identifying driver translocations, copy number alterations, and other genetic targets for trending disease state and response to treatment. Digital droplet PCR is the most widely used and appears to be the most efficient method. Further analysis will integrate the results with the aims of standardizing ctDNA use in EWS management.

Citation Format: Keval Yerigeri. Circulating tumor DNA as a prognostic, diagnostic, and clinical assessment tool for evaluation and management of Ewing's sarcoma: a systematic review [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 B072.
Abstract B073: MOMP-dependent cytotoxicity and immunogenicity of radiation therapy in breast cancer
Authors: Beltrán-Visiedo Manuel , Soler-Agesta Ruth , Guilbaud Emma , Sato Ai , Galluzzi Lorenzo
Published: February 2025

In 2023, an estimated 297,790 new cases of invasive breast cancer (BC) have been diagnosed to women in the US, causing an estimated 55,720 deaths, most of which originated from hormone receptor (HR+) BC. In this sense, radiation therapy (RT) has attracted attention as a potential tool to convert HR+ BCs that are scarcely infiltrated by immune cells (so-called ‘cold’) into highly infiltrated (so-called ‘hot’) immune checkpoint blockers (ICB)-responsive tumors thanks, among other factors, to the release of damage-associated molecular patterns (DAMPs), which promote the recognition of cancer cell death as immunogenic. In line with this notion, RT has been shown to positively interact with ICBs in preclinical models of mammary carcinoma, melanoma, glioma and glioblastoma, among others. Mitochondrial outer membrane permeabilization (MOMP) as mediated by BCL2 associated X, apoptosis regulator (BAX) and BCL2 antagonist/killer 1 (BAK1) and antagonized by BCL2, apoptosis regulator (BCL2) has been shown to regulate both the cytotoxicity and immunostimulatory potential of various anticancer agents. Here, we harnessed mouse mammary carcinoma TS/A cells bearing genetic alterations that affect the molecular machinery for MOMP to demonstrate their implications in the cytotoxic effect of RT and short-term release of the cell death-related DAMPs. In our hands, RT did not induce cell death in Bax -/- Bak1 -/- TS/A cells 48 h after exposition and in contrast to wild type (WT) cells, but it completely stopped their proliferation. Moreover, (1) MOMP defects failed to alter the ability of RT to elicit the immunogenic cell death (ICD)-associated exposure of calreticulin (CALR) on the outer leaflet of the plasma membrane. Additionally, (2) MOMP-deficient cells completely reduced their ability to release ATP after RT and (3) increased the levels of the co-inhibitory ligand CD274 (best known as PD-L1) on their surface in contrast to WT cells. These results highlighted the potential involvement of MOMP in the immunogenicity of RT-driven cell death.

Citation Format: Manuel Beltrán-Visiedo, Ruth Soler-Agesta, Emma Guilbaud, Ai Sato, Lorenzo Galluzzi. MOMP-dependent cytotoxicity and immunogenicity of radiation therapy in breast cancer [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 B073.
Abstract B076: Analyzing Hematological Parameters in Diabetes: Toward a Better Understanding of Pathophysiology
Authors: Rahman Nuran , Hira Israt Jahan , Fakruddin Md , Meheki Farha Rahman , Sharif Omar
Published: February 2025

Objectives: A person with diabetes is more prone to have dangerous diseases like cardiovascular disease, anemia, cancer, and COVID-19, which can be associated with modified levels of hematological markers. This research aims to find differences in hematological parameters and comorbidity factors in Bangladeshi diabetic patients. Methods: This 134-patient institutional cross-sectional comparison study included 62 patients with diabetes and 72 non-diabetic patients. Data on diabetes profile and hematological parameters has been collected from the study populations. Data were collected over a period from January 2023 to August 2023, with the analysis conducted subsequently. Statistical analysis was conducted using IBM SPSS Statistics version 29 software. P-value of (p<0.05) was deemed statistically significant. We did a correlation matrix between variables using Python data visualization libraries. Results: This study showed patients with diabetes may experience changes in hematological parameters. An independent T-test showed that the mean and standard deviation of WBC, ESR, mean platelet volume, etc, are statistically significant (p<0.05). Contrarily, other parameters like RBC, neutrophil, platelet, RDW-CV, etc, are shown to be statistically not significant (p>0.05) in diabetic patients as compared to the control non-diabetic group. Acute diseases had the highest percentage of severity with a number of 39 (38.7%). We found hypertension highest in the case of disease, with a percentage of 31 (22.08%) in diabetic patients and 25 (18.05%) in nondiabetic control patients. In the correlation matrix between all the possible pairs of hematological correlation coefficient, where (1) was considered a strong relationship between variables and (-1) a not strong relationship, we found positive correlation and negative correlation. Conclusion: Our study shows diabetic patients may undergo significant alterations in hematological parameters, resulting in a decrease in hemoglobin to anemia and an increase in WBC for an asymptomatic infection. This undiagnosed stage can be an alliance for injurious comorbidity factors. Diabetic patients should prescreened for hematological parameters before other tests.

Citation Format: Nuran Rahman, Israt Jahan Hira, Md Fakruddin, Farha Rahman Meheki, Omar Sharif. Analyzing Hematological Parameters in Diabetes: Toward a Better Understanding of Pathophysiology [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 B076.
Abstract B078: APMAP functions as a tumor-intrinsic target sensitizing cancer cells to macrophage-mediated phagocytosis
Authors: Davidson Rachel , Wang Ye , Ji Lei , Trombley Grace , Zhou Wenrong , Shen Binzhang , Choi Ashley , Stowe Hannah , Liu Shangtao , Meier Samuel R. , Doyon Brian , Whittington Douglas A. , Yu Yi , Teng Teng , Andersen Jannik N. , Huang Alan , Min Chengyin , Shaaban Salam , Gueroussov Serge
Published: February 2025

Macrophage-mediated phagocytosis plays a critical role in cancer cell elimination. Here, we developed an in vitro tumor-macrophage co-culture platform for unbiased identification of factors that impede macrophage phagocytosis using genome-wide CRISPR knockout. From the functional genomics screen, we identified APMAP as a tumor-intrinsic phagocytosis sensitizer. In vitro experiments validated that APMAP depletion in tumor cells enhances direct engulfment and selective killing of tumor cells by macrophages. In vivo experiments showed that APMAP depletion attenuates tumor growth and displays combinational effects with cetuximab in an MDA-MB-468 orthotopic model. To dissect the mechanism of action, we conducted a whole genome anchor screen using an APMAP-WT/KO isogenic pair and identified fatty acid biosynthesis pathway genes (including FASN, ACLY and ACC) that are required for APMAP deficiency-induced phenotypes; the metabolomics analysis suggests that sphingolipids are potential APMAP substrates. To inform drug discovery, we demonstrated that enzymatic activity is required for APMAP-enhanced phagocytosis. We further demonstrated that as a transmembrane protein, intracellularly localized APMAP was functional as a phagocytosis sensitizer, thereby suggesting that a small molecule inhibitor is preferred over a blocking antibody as a therapeutic strategy for disrupting APMAP activity.

Citation Format: Rachel Davidson, Ye Wang, Lei Ji, Grace Trombley, Wenrong Zhou, Binzhang Shen, Ashley Choi, Hannah Stowe, Shangtao Liu, Samuel R. Meier, Brian Doyon, Douglas A. Whittington, Yi Yu, Teng Teng, Jannik N. Andersen, Alan Huang, Chengyin Min, Salam Shaaban, Serge Gueroussov. APMAP functions as a tumor-intrinsic target sensitizing cancer cells to macrophage-mediated phagocytosis [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 B078.
Abstract B081: Characterizing immune dysregulation and tertiary lymphoid structures in endometriosis: Pathogenic insights and therapeutic implications
Authors: Rahman Ariana F , Khazaie Khashayarsha , Javaheri Elika , Woldeamanuel Yohannes
Published: February 2025

Endometriosis (EMS) is a prevalent systemic disorder impacting 10% of women of reproductive age, characterized by the growth of endometrial-like tissue outside the uterine cavity, chronic inflammation, and fibrosis, leading to pain, infertility, and organ dysfunction. Despite its widespread occurrence, the pathogenesis of EMS remains elusive, and current treatments are inadequate, with recurrence post-surgery being a significant issue. Notably, EMS displays features reminiscent of malignancy, including genetic mutations and clonal cell proliferation. The presence of tertiary lymphoid structures (TLSs) within lesions indicates a potential role of immune dysfunction in disease progression. This study aims to explore immune mechanisms underlying EMS through three specific aims: 1) Analyzing cellular, molecular, and spatial characteristics of T and B cell interactions; 2) Defining the functional phenotype of immune cells involved; and 3) Investigating the B cell antigen receptor repertoire and the specificity of locally produced antibodies. Techniques such as single-cell RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence, are employed. The outcomes provide insights into immune contributions to EMS pathology and guide the development of novel diagnostic and therapeutic strategies.

Citation Format: Ariana F Rahman, Khashayarsha Khazaie, Elika Javaheri, Yohannes Woldeamanuel. Characterizing immune dysregulation and tertiary lymphoid structures in endometriosis: Pathogenic insights and therapeutic implications [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 B081.
Abstract B087: Comparative Efficacy of Pomalidomide vs. Teclistamab in Preventing AL Amyloidosis Progression in Refractory Multiple Myeloma
Authors: Seylani Allen , Haile Yohannes , Sadighian Assal
Published: February 2025

Background: AL amyloidosis progression is a critical complication in patients with refractory multiple myeloma (MM), leading to poor outcomes. Pomalidomide, an immunomodulatory drug, and Teclistamab, a bispecific antibody targeting BCMA, are both used in the management of refractory MM. This study compares the efficacy of Pomalidomide versus Teclistamab in preventing the progression of AL amyloidosis in this patient population. Methods: We conducted a retrospective cohort study utilizing de-identified patient data from the TriNetX platform, which comprises electronic health records (EHRs) from 157 million patients across 128 healthcare systems in 18 countries. The study focused on 1,560 patients with relapsed/refractory multiple myeloma, comparing AL amyloidosis progression in those treated with Pomalidomide (n=779) versus Teclistamab (n=781). The primary outcome assessed was the risk of AL amyloidosis progression during treatment with Pomalidomide vs. Teclistamab. Propensity score matching was employed to balance baseline characteristics, including age, sex, ethnicity, and comorbidities, between the two cohorts. Results: In the Pomalidomide-treated group, 17 patients experienced AL amyloidosis progression, yielding a risk of 2.18%. In the Teclistamab-treated group, 12 patients had disease progression, with a risk of 1.38%. While Teclistamab demonstrated a lower risk compared to Pomalidomide, the difference was not statistically significant (p=0.1720). The calculated risk ratio (RR) was 1.704 (95% CI: 0.785, 3.699). Conclusion: Although Teclistamab showed a numerically lower risk of AL amyloidosis progression compared to Pomalidomide, the difference did not reach statistical significance. This preliminary result may be due to inadequate data available regarding Teclistamab use since Teclistamab is a new therapeutic approved by the FDA in October of 2022. Further prospective studies are warranted to evaluate the potential superior protective effect of Teclistamab against AL amyloidosis in refractory multiple myeloma, highlighting the necessity for additional research to optimize therapeutic strategies for this high-risk population.

Citation Format: Allen Seylani, Yohannes Haile, Assal Sadighian. Comparative Efficacy of Pomalidomide vs. Teclistamab in Preventing AL Amyloidosis Progression in Refractory Multiple Myeloma [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 B087.
Abstract B101: Classification based on intratumoral microbiome confer the molecular characteristics and immune microenvironment in gastric cancer
Authors: Oh Han Na , Hur Hoon
Published: February 2025

Gastric cancer (GC) with the immuno-activating tumor microenvironment (TME) significantly correlated with better oncologic outcomes or response to immunotherapy. Increasing evidence suggests that intratumoral microbiome promote carcinogenesis or tumor progression by genetic instability and remodeling of the immune landscape and oncogenic signals. However, the correlation between intratumoral microbiome and genetic or immune profiling has not been clearly disclosed in GC. To capture the complexity of bacterial composition within GC and its TME, we analyzed The Cancer Microbiome Atlas (TCMA)-public data from 100 GC patients, including bacterial abundance profiles, bulk RNA sequencing, CIBERSORT, and DNA mutation in this study. Using partitioning around medoids (PAM) clustering, we classified GC microbiome structures into four distinct types based on dominant bacterial genera: Lactobacillus, Helicobacter, Prevotella, and Streptococcus. By using rcorr-based Pearson’s correlation analysis and Redundancy Analysis (RDA), we found that association of intratumor microbiome with immune cell proportion and cancer gene mutation. The Lactobacillus-dominant type exhibited both bacteria-immune cell and bacteria-bacteria interactions with upregulation of bacterial invasion of epithelial cells, and the Streptococcus-dominant type showed downregulation of gastric acid secretion pathways. While, the Prevotella-dominant type was characterized by higher abundance of activated memory CD4 T cells, CD8 T cells, M1 macrophages than other types, especially Streptococcus-dominant type, and also associated with KRAS mutations. It implies that intratumoral Prevotella-dominant type play a role of immune activation in the TME. This study demonstrated that a specific intratumoral microbiome cluster, Prevotella-dominant type, may promote immune activation of TME in patients with GC. Overall, this study provides insights into the potential impact of specialized intratumoral microbiomes on the TME in GC patients.

Citation Format: Han Na Oh, Hoon Hur. Classification based on intratumoral microbiome confer the molecular characteristics and immune microenvironment in gastric cancer [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 B101.
Abstract B104: Comparative Efficacy of Pomalidomide vs. Teclistamab in Preventing AL Amyloidosis Progression in Refractory Multiple Myeloma
Authors: Seylani Allen , Haile Yohannes , Sadighian Assal
Published: February 2025

Background: AL amyloidosis progression is a critical complication in patients with refractory multiple myeloma (MM), leading to poor outcomes. Pomalidomide, an immunomodulatory drug, and Teclistamab, a bispecific antibody targeting BCMA, are both used in the management of refractory MM. This study compares the efficacy of Pomalidomide versus Teclistamab in preventing the progression of AL amyloidosis in this patient population. Methods: We conducted a retrospective cohort study utilizing de-identified patient data from the TriNetX platform, which comprises electronic health records (EHRs) from 152 million patients across 128 healthcare systems in 18 countries. The study focused on 1,560 patients with relapsed/refractory multiple myeloma, comparing AL amyloidosis progression in those treated with Pomalidomide (n=779) versus Teclistamab (n=781). The primary outcome assessed was the risk of AL amyloidosis progression during treatment with Pomalidomide vs. Teclistamab. Propensity score matching was employed to balance baseline characteristics, including age, sex, ethnicity, and comorbidities, between the two cohorts. Results: In the Pomalidomide-treated group, 17 patients experienced AL amyloidosis progression, yielding a risk of 2.18%. In the Teclistamab-treated group, 12 patients had disease progression, with a risk of 1.38%. While Teclistamab demonstrated a lower risk compared to Pomalidomide, the difference was not statistically significant (p=0.1720). The calculated risk ratio (RR) was 1.704 (95% CI: 0.785, 3.699). Conclusion: Although Teclistamab showed a numerically lower risk of AL amyloidosis progression compared to Pomalidomide, the difference did not reach statistical significance. Further prospective studies are warranted to determine whether Teclistamab offers a superior protective effect against AL amyloidosis in refractory multiple myeloma. These findings highlight the need for additional research to optimize therapeutic strategies for this high-risk population.

Citation Format: Allen Seylani, Yohannes Haile, Assal Sadighian. Comparative Efficacy of Pomalidomide vs. Teclistamab in Preventing AL Amyloidosis Progression in Refractory Multiple Myeloma [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 B104.
Abstract B115: Epithelial stromal interaction 1 protein (ESPTI1) expression in breast cancers with known estrogen receptor, progesterone receptor and human epidermal growth receptors-2 immunoreactivity: Any prognostic indication?
Authors: Ogenyi Samuel Ifedioranma , Ezenwa Bruno Onochie , Onu June Amara , Ike Amalachukwu Okwukwe , Okoye Jude Ogechukwu , Ogenyi Samuel Ifedioranma
Published: February 2025

Background: The heterogeneous nature of breast cancers has shifted the focus from pathogenesis, and clinicopathological correlations to prognostication; with increased attention being paid to identifying morphological features and biomarkers of prognostic significance. Objective: This study evaluated the expression pattern of EPSTI1protein biomarker in breast cancers with known Estrogen, Progesterone, and Human epidermal receptors (Her-2-neu) immunoreactivity. Methods: One hundred archived formalin fixed-paraffin embedded (FFPE) diagnosed breast cancer samples involving sixty-two triple-negative breast cancers (TNBC) and thirty-eight other breast cancer groups comprising mono negatives, bi negatives and triple positives were retrieved from the archives of the Department of Histopathology, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria. Real-time polymerase chain reaction (RT-PCR) of EPSTI1 was performed to determine EPSTI1 expression levels while immunohistochemistry was employed to determine ER, PR and Her-2 reactivity. Results: An increasing expression pattern of EPSTI1 in an ascending order ranging from triple-positive to triple-negative breast cancers was revealed. There was a significant increase in EPSTI1 levels in mono-negative cancers compared to mono-negative cancers. Similarly, a strong negative association between triple positive and triple negative cancers and mono positive and mono negative lesions were noted. Conclusion: The study revealed an inverse relationship between EPST1 and hormonal receptor expressions. EPST1 expression characterization of breast cancers may be explored further as a formidable prognostic and therapeutic biomarker for the more aggressive triple-negative breast cancers.

Citation Format: Samuel Ifedioranma Ogenyi, Bruno Onochie Ezenwa, June Amara Onu, Amalachukwu Okwukwe Ike, Jude Ogechukwu Okoye, Samuel Ifedioranma Ogenyi. Epithelial stromal interaction 1 protein (ESPTI1) expression in breast cancers with known estrogen receptor, progesterone receptor and human epidermal growth receptors-2 immunoreactivity: Any prognostic indication? [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 B115.
Abstract B124: Molecular mimicry of SARS-COV-2 antigens with tumor associated antigens
Authors: Ragone Concetta , Mauriello Angela , Cavalluzzo Beatrice , Cavalcanti Ernesta , Russo Luigi , Mangano Simona , Cembrola Biancamaria , Tagliamonte Maria , Buonaguro Luigi
Published: February 2025

The entire SARS-CoV-2 proteome was scanned to predict potential T cell antigens linked to HLA-A*02:01 and homology to TAAs (tumor-associated antigens) was searched by BLAST. Viral epitopes with high affinity (<100nM) to the HLA-A*02:01 allele were predicted. Shared and variant-specific epitopes were identified. Significant homologies in amino acidic sequence have been found between SARS-CoV-2 peptides and multiple TAAs, mainly associated with breast, liver, melanoma and colon cancers. The molecular mimicry of the viral epitopes and the TAAs was found in all viral proteins, mostly the Orf 1ab and the Spike, which is included in the BNT162b2 vaccine. Predicted structural similarities confirmed the sequence homology and comparable patterns of contact with both HLA and TCR α and β chains were observed. CD8+ T cell clones cross-reactive with the paired peptides have been found by MHC class l-dextramer staining. Our results show for the first time that several SARS-COV-2 antigens are highly homologous to TAAs and cross-reactive T cells are identified in infected and BNT162b2 preventive vaccinated individuals. The implication would be that the SARS-Cov-2 pandemic could represent a natural preventive immunization for breast, liver, melanoma and colon cancers. In the coming years, real-world evidences will provide the final proof for such immunological experimental evidence. Moreover, such SARS-CoV-2 epitopes can be used to develop “multi-cancer” off-the-shelf preventive/therapeutic vaccine formulations, with higher antigenicity and immunogenicity than over-expressed tumor self-antigens, for the potential valuable benefit of thousands of cancer patients around the World. Ragone et al., Front. Immunol. 15:1398002

Citation Format: Concetta Ragone, Angela Mauriello, Beatrice Cavalluzzo, Ernesta Cavalcanti, Luigi Russo, Simona Mangano, Biancamaria Cembrola, Maria Tagliamonte, Luigi Buonaguro. Molecular mimicry of SARS-COV-2 antigens with tumor associated antigens [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 B124.
Abstract B125: SARS-CoV-2 mRNA vaccines sensitize tumors to immune checkpoint blockade
Authors: Grippin Adam , Marconi Christiano , Copling Sage , Mendez-Gomez Hector , Wargo Jennifer , Heymach John , Jiang Wen , Sayour Elias , Lin Steven H
Published: February 2025

Although immune checkpoint inhibitors (ICI) have substantially extended survival in a subset of patients with cancer, they remain ineffective in most patients. Personalized mRNA vaccines sensitize tumors to ICIs in part by unleashing a cytokine/chemokine cascade that broadly activates immune cells. Since this cascade is not dependent on mRNA species, we hypothesized that mRNA vaccines encoding non-tumor-specific antigens might also be used to reset immunotolerance and sensitize response to ICIs. Here, we show that mRNA vaccines targeting SARS-CoV-2 spike protein dramatically augment responses to ICIs. In two cohorts of patients with non-small cell lung cancer and metastatic melanoma, receipt of a COVID mRNA vaccine within 100 days of ICI initiation was associated with near doubling of overall survival after controlling for over 38 covariates with Cox Proportional Hazards Regression. Preclinical models confirmed that mRNA vaccines targeting SARS-COV-2 sensitize response to ICIs. By inducing a surge in interferon-α and Th1 chemokines, spike mRNA vaccines mediate antigen presenting cell co-localization with T cells in lymphoid organs for induction of anti-tumor immunity. Due to increases in PD-L1 on tumor cells, concomitant ICI treatment elicits increased PD-1+ T cells and epitope spreading against cancer associated antigens. Similar correlates of response were seen in both patients and healthy volunteers. Together, these results demonstrate that clinically available mRNA vaccines targeting non-tumor antigens are potent immune modulators capable of sensitizing tumors to ICIs.

Citation Format: Adam Grippin, Christiano Marconi, Sage Copling, Hector Mendez-Gomez, Jennifer Wargo, John Heymach, Wen Jiang, Elias Sayour, Steven H Lin. SARS-CoV-2 mRNA vaccines sensitize tumors to immune checkpoint blockade [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 B125.
Abstract IA01: Longitudinal landscape analysis of the neoantigen-specific T-cell responses in patients with melanoma with or without response to PD1 blockade
Authors: Puig Saus Cristina
Published: February 2025

T-cell responses induced by immune checkpoint blockade therapy target, among others, neoantigens derived from non-synonymous mutations. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T-cell responses in patients over their treatment course. In this educational session, we will discuss a recently developed technology that allows the capture of low-frequency neoantigen-specific T cells and its application to characterize the neoantigen-specific T-cell responses in the blood and tumor from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. This approach uses personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T-cell receptors. Our results show that multiple T cells with different TCR sequences (T-cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These TCR clonotypes were recurrently detected over time in the blood and tumor. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T-cell responses in the blood and tumor to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoantigen-specific TCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Our results show that effective anti-PD-1 immunotherapy is associated with a polyclonal CD8+ T-cell response in the tumor and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Citation Format: Cristina Puig Saus. Longitudinal landscape analysis of the neoantigen-specific T-cell responses in patients with melanoma with or without response to PD1 blockade [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 IA01.
Abstract IA04: New developments in drugging the adenosine pathway
Authors: Jaen Juan C
Published: February 2025

Adenosine is a pleiotropic immunosuppressive substance, produced mainly by the enzymes CD39 and CD73, from extracellular immunogenic ATP. Thus, CD73-rich tumors may experience decreased anti-tumor immune activity when treated with immunogenic chemotherapies (e.g., platinum-based drugs), relative to what might be possible in the absence of adenosine. From a therapeutic perspective, potential drugs that aim to interfere with the production or signaling of adenosine need to be potent and selective enough, under physiological conditions, to overcome the large amount of adenosine present in selected tumors. Recent results from several clinical studies are strongly supportive of the anti-cancer potential stemming from inhibition of the adenosine axis, when drug properties, tumor selection/setting, and combination backbones are taken into account. This presentation will briefly highlight key design elements for two such drugs, etrumadenant (a dual blocker of A2a and A2b adenosine receptors) and quemliclustat (a CD73 inhibitor), as well as recent clinical results with these agents in advanced colorectal cancer (CRC; ARC-9) and pancreatic cancer (PDAC; ARC-8), respectively. We will also describe how drug-related changes in markers of adenosine activity, as well as baseline levels of those markers, are associated with clinical outcomes in these trials.

Citation Format: Juan C Jaen. New developments in drugging the adenosine pathway [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 IA04.
Abstract IA05: KRAS inhibitors and modulation of inflammation and immunity
Authors: Vonderheide Robert H
Published: February 2025

The desire to target mutant KRAS therapeutically is now being realized with more and more broadly applicable and allele-specific molecular inhibitors entering clnical trials and gaining FDA approval. Tumor KRAS signaling plays a major role in orchestrating tumor immunosuppression leaving mutant KRAS inhibitors with the potential for immune modulation that could be synergistic with immuno oncology strategies. Here, data will be presented regarding the immune mechanisms and T cell dependency of KRAS inhibitors and their ability to work in concert with checkpoint blockade and CD40 activation for durable tumor regresssions.

Citation Format: Robert H Vonderheide. KRAS inhibitors and modulation of inflammation and immunity [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 IA05.