Role Of Tumor Microenvironment Research Articles

Role of Tumor Microenvironment in the Risk of Thromboembolic Complications in Ovarian Cancer

Introduction. Incidence of ovarian cancer remains high in the overall prevalence of oncological pathology. Adjuvant chemotherapy refers to its treatment options. Patients with oncological pathology are faced with a high risk of thrombosis and thromboembolism, with up to 30% lethal outcome within a month of its development. A number of cancer cells are known to induce platelet aggregation, contributing to thrombosis and metastasis as a result of this interaction. Accordingly, the paper is aimed at presenting a clinical case for demonstrating the role of P-selectin expression in the complications in a patient with ovarian cancer. Materials and methods. The present paper evaluates platelet activation marker in a patient undergoing chemotherapy courses after cytoreductive surgery. Following the case conference and in accordance with the clinical recommendations of the Russian Oncology Association (AOR) and Russian Society of Clinical Oncology (RUSSCO), cytoreduction (CC-0), radical hysterectomy, transverse colectomy, left hemicolectomy with rectum resection were performed. The interventions included ascendostomy, pelvic, lateral right-sided and left-sided peritonectomy, pelvic lymphoadenectomy, total omentectomy, Renape-French HIPEC (hyperthermic intraperitoneal chemotherapy), abdominal and pelvic drainage. Expression of P-selectin on the platelet surface was measured as a marker of platelet activation. Results and discussion. At the time of admission, the patient had high CD62 expression activity compared to healthy volunteers (CD62 ADP- — 11.2%, CD62 ADP — 24.7% vs CD62 ADP- — 1.3%, CD62 ADP — 17.2%). During the complex treatment of ovarian cancer, the platelet activation increased (CD62 ADP- — 21.8 %, CD62 ADP+ — 30.1 %). At discharge, CD62 expression values reached the conditional norm, presumably indicating thrombosis development. Conclusion. Tumor microenvironment influences the hemostasis system. Detailed study into this issue obtains a high potential for the prevention of primary and secondary thromboembolic complications in oncologic patients.

Tumor microenvironment as a complex milieu driving cancer progression: a mini review.

It has been spotlighted that the Tumor Microenvironment (TME) is crucial for comprehending cancer progression and therapeutic resistance. Therefore, this comprehensive review elucidates the intricate architecture of the TME, which encompasses tumor cells, immune components, support cells, and a myriad of bioactive molecules. These constituents collectively foster dynamic interactions that underpin tumor growth, metastasis, and nuanced responses to anticancer therapies. Notably, the TME's role extends beyond mere physical support, serving as a critical mediator in cancer-cell evolution, immune modulation, and treatment outcomes. Innovations targeting the TME, including strategies focused on the vasculature, immune checkpoints, and T-cell therapies, have forged new pathways for clinical intervention. However, the heterogeneity and complexity of the TME present significant challenges, necessitating deeper exploration of its components and their interplay to enhance therapeutic efficacy. This review underscores the imperative for integrated research strategies that amalgamate insights from tumor biology, immunology, and systems biology. Such an approach aims to refine cancer treatments and improve patient prognoses by exploiting the TME's complexity.

Molecular subtypes and nomogram for predicting the prognosis of cervical cancer based on a matrix-immune signature

Cervical cancer is a kind of tumor related to chronic HPV infection. Currently, the treatment of cervical cancer is guided mainly by clinicopathological factors. The role of tumor microenvironment in the prognosis and treatment of cervical cancer has been ignored. We aimed to use bioinformatics to identify the molecular subtypes in cervical cancer and construct a predictive nomogram combining a matrix-immune signature (MIS) and clinicopathological factors to support treatment decisions. Two cervical cancer subtypes with different prognoses were identified based on matrix- and immune-genes in TCGA-CESC. The MIS was developed using Cox regression and Lasso algorithm and verified in the Cancer Genome Characterization Initiative (CGCI) using time-dependent receiver operating characteristic (ROC) curve analysis. Multivariable analysis identified lymph node metastases, lymphovascular space invasion, and the MIS as independent prognostic factors, which were used to construct the predictive nomogram. The areas under the ROC curve of the model were 0.872, 0.879, and 0.803 for the 1-, 3-, and 5-year periods, respectively. The C-index was 0.845. Calibration curves confirmed the excellent prognosis prediction of the nomogram. The nomogram indicted a 3-year survival rate of > 90% in patients with a total score > 110.1. The constructed predictive nomogram has significant implications for prognostic assessment and treatment selection in cervical cancer.

The Role of Tumor Microenvironment in Pancreatic Cancer Immunotherapy: Current Status and Future Perspectives.

Pancreatic cancer comprises different subtypes, where most cases include ductal adenocarcinoma (PDAC). It is one of the deadliest tumor types, with a poor prognosis. In the majority of patients, the disease has already spread by the time of diagnosis, making full recovery unlikely and increasing mortality risk. Despite developments in its detection and management, including chemotherapy, radiotherapy, and targeted therapies as well as advances in immunotherapy, only in about 13% of PDAC patients does the overall survival exceed 5 years. This may be attributed, at least in part, to the highly desmoplastic tumor microenvironment (TME) that acts as a barrier limiting perfusion, drug delivery, and immune cell infiltration and contributes to the establishment of immunologically 'cold' conditions. Therefore, there is an urgent need to unravel the complexity of the TME that promotes PDAC progression and decipher the mechanisms of pancreatic tumors' resistance to immunotherapy. In this review, we provide an overview of the major cellular and non-cellular components of PDAC TME, as well as their biological interplays. We also discuss the current state of PDAC therapeutic treatments and focus on ongoing and future immunotherapy efforts and multimodal treatments aiming at remodeling the TME to improve therapeutic efficacy.

Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment.

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells' metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. New strategies target TME genetic alterations and specific pathways in cell populations of the TME. Complex molecular interactions develop between PDAC cells and TME cell populations including cancer-associated fibroblasts, myeloid-derived suppressor cells, pancreatic stellate cells, tumor-associated macrophages, tumor-associated neutrophils, and regulatory T cells. In the present review, we aim to fully explore the molecular landscape of the pancreatic cancer TME cell populations and discuss current TME targeting strategies to provide thoughts for further research and preclinical testing.

Elevated expression of Golgi Transport 1B promotes the progression of cervical cancer by activating NF-κB signaling pathway via interaction with TBK1.

As a preventable disease, cervical cancer (cervical squamous cell carcinoma and endocervical adenocarcinoma - CESC) remains a tumor with high morbidity and mortality worldwide, underscoring the pressing need for effective treatment strategies. This research identified Golgi transport 1B (GOLT1B) as a critical gene involved in the development of cervical cancer. Gene Expression Omnibus (GEO) datasets were investigated to determine the upregulation of GOLT1B in cervical cancer tissue compared to normal tissue. Besides, GOLT1B was found to predict poor prognosis in cervical cancer by utilizing Gene Expression Profiling Interactive Analysis (GEPIA). The functional assay indicated that GOLT1B promoted CESC viability and migration in vitro and in vivo. RNA sequencing results suggested that GOLT1B likely influenced NF-κB pathway. The subsequent western blot and dual luciferase reporter assay revealed the interaction between GOLT1B and TBK1, modulating the NF-κB pathway. More importantly, GOLT1B was also found to regulate immune cells infiltration, suggesting its potential role in tumor microenvironment. In conclusion, GOLT1B promotes CESC progression via interaction with TBK1 and augmentation of NF-κB signaling-mediated cancer-associated inflammation, which provides us a new approach to CESC target therapy.

Glycolysis-related genes predict prognosis and indicate immune microenvironment features in gastric cancer.

Gastric cancer (GC) is a major contributor to cancer-related mortality. Glycolysis plays a pivotal role in tumor microenvironment (TME) reprogramming. In this research, the functions of glycolysis-associated genes (GRGs) were evaluated to predict the outcome and reveal the characteristics of the immune microenvironment in individuals with stomach cancer. The Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD) cohort provided gene expression and clinical data for gastric cancer (GC) patients, which were further authenticated using datasets sourced from the Gene Expression Omnibus (GEO). By referencing the Molecular Signatures Database (MSigDB), a total of 326 GRGs were pinpointed. The various subtypes of GC were outlined through consensus clustering, derived from the expression patterns of these GRGs. Utilizing multivariate Cox regression analysis, a multigene risk score model was formulated. Both the CIBERSORT and ESTIMATE algorithms played a pivotal role in assessing the immune microenvironment. To delve into the biological functions of the key genes, wound healing, transwell invasion, and MTT assays were conducted. Based on the expression patterns of GRGs, patients were categorized into two distinct groups: the metabolic subtype, designated as cluster A, and the immune subtype, labeled as cluster B. Patients belonging to cluster B exhibited a poorer prognosis. A prognostic risk score model, formulated upon the expression levels of six key GRGs - ME1, PLOD2, NUP50, CXCR4, SLC35A3, and SRD35A3 - emerged as a viable tool for predicting patient outcomes. The downregulation of CXCR4 notably diminished the glycolytic capacity of gastric cancer (GC) cells, alongside their migratory, invasive, and proliferative capabilities. Intriguingly, despite the adverse prognostic implications associated with both the immune subtype (cluster B) and the high-risk cohort, these groups exhibited a favorable immune microenvironment coupled with elevated expression of immune checkpoint genes. Our investigations revealed a positive correlation between high CXCR4 expression and low ME1 expression with the infiltration of CD8+ T cells, as well as an enhanced responsiveness to treatment with an anti-PD-1 immune checkpoint inhibitor. In this study, we discovered that the expression profiles of GRGs hold the potential to forecast the prognosis of gastric cancer (GC) patients, thereby possibly aiding in clinical treatment decision-making.

Integrative analysis of ferroptosis-related genes reveals that ABHD12 is a novel prognostic biomarker and facilitates hepatocellular carcinoma tumorigenesis

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, making the prognostic prediction challenging. Ferroptosis, an iron-dependent form of cell death, is a key regulator in the initiation, progression, and metastasis of HCC. However, the expression and function of ferroptosis-related genes (FRGs) in HCC remained largely unclear. In this study, we analyzed TCGA datasets and identified 58 survival-related deferentially expressed FRGs (DE-FRGs). Then, based on the results of LASSO analysis, we developed a novel prognostic model based on 12 survival-related DE-FRGs. Survival assays indicated a strong prognostic ability of this new model in predicting clinical prognosis of HCC patients. In addition, we conducted an exploration of molecular subtypes related to HCC and delved into the associated immune characteristics and gene expression patterns. Among the 12 survival-related DE-FRGs, our attention focused on ABHD12 (abhydrolase domain containing 12) which was highly expressed in HCC and associated with advanced clinical stages. Multivariate assays confirmed that ABHD12 was a significant prognostic factor for HCC patients. Immune analysis revealed that ABHD12 may play an important role in tumor microenvironment. Finally, we performed RT-PCR and confirmed that ABHD12 was highly expressed in HCC cells. Functional experiments revealed that ABHD12 knockdown may suppress the proliferation and migration of HCC cells. These findings emphasized the significance of ABHD12 as a potential prognostic marker for HCC and its crucial role in the field of tumor biology. Additionally, the study introduces a novel survival model that holds promise for enhancing prognostic predictions in HCC patients. Overall, this research provided valuable insights for a deeper comprehension of the complexity of HCC and the development of personalized treatment strategies.

Circadian rhythms and breast cancer: unraveling the biological clock's role in tumor microenvironment and ageing.

Breast cancer (BC) is one of the most common and fatal malignancies among women worldwide. Circadian rhythms have emerged in recent studies as being involved in the pathogenesis of breast cancer. In this paper, we reviewed the molecular mechanisms by which the dysregulation of the circadian genes impacts the development of BC, focusing on the critical clock genes, brain and muscle ARNT-like protein 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK). We discussed how the circadian rhythm disruption (CRD) changes the tumor microenvironment (TME), immune responses, inflammation, and angiogenesis. The CRD compromises immune surveillance and features and activities of immune effectors, including CD8+ T cells and tumor-associated macrophages, that are important in an effective anti-tumor response. Meanwhile, in this review, we discuss bidirectional interactions: age and circadian rhythms, aging further increases the risk of breast cancer through reduced vasoactive intestinal polypeptide (VIP), affecting suprachiasmatic nucleus (SCN) synchronization, reduced ability to repair damaged DNA, and weakened immunity. These complex interplays open new avenues toward targeted therapies by the combination of clock drugs with chronotherapy to potentiate the immune response while reducing tumor progression for better breast cancer outcomes. This review tries to cover the broad area of emerging knowledge on the tumor-immune nexus affected by the circadian rhythm in breast cancer.

The role of cancer-associated fibroblasts in the invasion and metastasis of colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and has ranked the third leading cause in cancerassociated death globally. Metastasis is the leading cause of death in colorectal cancer patients. The role of tumor microenvironment (TME) in colorectal cancer metastasis has received increasing attention. As the most abundant cell type in the TME of solid tumors, cancer-associated fibroblasts (CAFs) have been demonstrated to have multiple functions in advancing tumor growth and metastasis. They can remodel the extracellular matrix (ECM) architecture, promote epithelial-mesenchymal transition (EMT), and interact with cancer cells or other stromal cells by secreting growth factors, cytokines, chemokines, and exosomes, facilitating tumor cell invasion into TME and contributing to distant metastasis. This article aims to analyze the sources and heterogeneity of CAFs in CRC, as well as their role in invasion and metastasis, in order to provide new insights into the metastasis mechanism of CRC and its clinical applications.

Exploring the prognostic implications of cuproptosis-associated alterations in clear cell renal cell carcinoma via in vitro experiments

This study investigated the impact of novel copper ionophores on the prognosis of clear cell renal cell carcinoma (ccRCC) and the tumor microenvironment (TME). The differential expression of 10 cuproptosis and 40 TME-pathway-related genes were measured in 531 tumor samples and 71 adjacent kidney samples in The Cancer Genome Atlas database. A risk score model was constructed with LASSO cox to predict the prognosis of ccRCC patients. Forest plot and function enrichment were used to study the biological function of the key genes in depth. The study found that the risk score model accurately predicted the prognosis of ccRCC patients. Patients with high scores had higher immune responses with a higher proportion of anti-tumor lymphocytes and a lower proportion of immunosuppressive M2-like macrophages. However, the high-score group also exhibited a higher proportion of T follicular helper cells and regulatory T cells. These results suggest that cuproptosis-based therapy may be worth further investigation for the treatment of ccRCC and TME. Subsequently, by using RNAi, we established the stable depletion models of FDX1 and PDHB in ccRCC cell lines 786-O and ACHN. Through CCK8, colony formation, and Transwell assays, we observed that the knockdown of FDX1 and PDHB could significantly reduce the capabilities of proliferation and migration in ccRCC cells. In conclusion, this study illuminates the potential effectiveness of copper ionophores in the treatment of ccRCC, with higher risk scores correlating with better TME immune responses. It sets the stage for future cuproptosis-based therapy research in ccRCC and other cancers, focusing on copper’s role in TME.

Recent Clinical Implications of FAPI: Imaging and Therapy.

The fibroblast activation protein (FAP) is a biomarker that is selectively overexpressed on cancer-associated fibroblasts (CAFs) in various types of tumoral tissues and some nonmalignant diseases, including fibrosis, arthritis, cardiovascular, and metabolic diseases. FAP plays a critical role in tumor microenvironment through facilitating proliferation, invasion, angiogenesis, immunosuppression, and drug resistance. Recent studies reveal that FAP might be regarded as a promising target for cancer diagnosis and treatment. FAP-targeted imaging modalities, especially PET, have shown high sensitivity and specificity in detecting FAP-expressing tumors. FAP-targeted imaging can potentially enhance tumor detection, staging, and monitoring of treatment response, and facilitate the development of personalized treatment strategies. This study provides a comprehensive view of FAP and its function in the pathophysiology of cancer and nonmalignant diseases. It also will discuss the characteristics of radiolabeled FAP inhibitors, particularly those based on small molecules, their recent clinical implications in imaging and therapy, and the associated clinical challenges with them. In addition, we present the results of imaging and biodistribution radiotracer 68Ga-FAPI-46 in patients with nonmalignant diseases, including interstitial lung disease, primary biliary cirrhosis, and myocardial infarction, who were referred to our department. Our results show that cardiac FAP-targeted imaging can provide a novel potential biomarker for managing left ventricle remodeling. Moreover, this study has been organized and presented in a manner that offers a comprehensive overview of the current status and prospects of FAPI inhibitors in the diagnosis and treatment of diseases.

PFDA promotes cancer metastasis through macrophage M2 polarization mediated by Wnt/β-catenin signaling

Perfluoroundecanoic acid (PFDA) is extensively utilized in the textile and food processing industries and may have a tumor-promoting effect by modulating the tumor microenvironment. Macrophages play crucial roles in tumor microenvironment as key regulators of tumor immunity. However, further investigation is needed to elucidate how PFDA interacts with macrophages and contributes to tumor progression. In this study, we treated the macrophage cell line RAW264.7 with various concentrations of PFDA and found that RAW264.7 transitioned into an M2 tumor-promoting phenotype. Through bioinformatic analysis and subsequent verification of molecular assays, we uncovered that PFDA could activate β-catenin and enhance its nuclear translocation. Additionally, it was also observed that inhibiting β-catenin nuclear translocation partly attenuated RAW264.7 M2 polarization induced by PFDA. The conditioned medium derived from PFDA-pretreated RAW264.7 cells significantly promoted the migration and invasion abilities of human ovarian cancer cells. Furthermore, in vivo studies corroborated that PFDA-pretreated RAW264.7 could promote tumor metastasis, which could be mitigated by pretreatment with the β-catenin inhibitor ICG001. In conclusion, our study demonstrated that PFDA could promote cancer metastasis through regulating macrophage M2 polarization in a Wnt/β-catenin-dependent manner.

Decoding the Expressions, Immune Relevance, and Prognostic Values of Ferroptosis Gene TMEM189: A Pan-Cancer Analysis.

TMEM189 is a recently discovered transmembrane protein involved in ether glycerophospholipid synthesis and ferroptosis regulation. However, its role in tumors are not well understood. To elucidate the oncogenic effects and prognostic values of TMEM189 in tumors. We performed a pan-cancer analysis of TMEM189 using various databases, bioinformatics and statistical tools, and tissue microarray analysis. TMEM189 is generally upregulated in tumors compared to normal tissues. High TMEM189 expression is linked to reduced promoter methylation. TMEM189 exhibits a negative correlation with immunogenic markers, immune cell infiltration, and expression of immune checkpoint genes (ICGs) in most cancers, implicating its immunosuppressive role in tumor microenvironments (TME). The interacting and similar genes with TMEM189 were involved in hotspot signaling pathways in pan-cancer. TMEM189 overexpression is usually associated with poor prognosis, especially an independent prognostic risk factor for BLCA, BRCA, LUAD, MESO, LIHC and SKCM. TMEM189 is overexpressed and exerts immunosuppressive effects in many tumors with a significant association with poor prognosis, suggesting its potential as a therapeutic target in cancer treatment.

Advances in Hodgkin Lymphoma Treatment: From Molecular Biology to Clinical Practice.

Classical Hodgkin Lymphoma (cHL) is a highly curable disease, but around 20% of patients experience progression or relapse after standard frontline chemotherapy regimens. Salvage regimens followed by autologous stem cell transplants represent the historical treatment approach for these cases. In the last decade, with the increasing understanding of cHL biology and tumor microenvironment role in disease course, novel molecules have been introduced in clinical practice, improving outcomes in the relapsed/refractory setting. The anti-CD30 antibody-drug conjugated brentuximab vedotin and PD-1/PD-L1 checkpoint inhibitors represent nowadays curative options for chemorefractory patients, and randomized trials recently demonstrated their efficacy in frontline immune-chemo-combined modalities. Several drugs able to modulate the patients' T-lymphocytes and NK cell activity are under development, as well as many anti-CD30 chimeric antigen receptor T-cell products. Multiple tumor aberrant epigenetic mechanisms are being investigated as targets for antineoplastic compounds such as histone deacetylase inhibitors and hypomethylating agents. Moreover, JAK2 inhibition combined with anti-PD1 blockade revealed a potential complementary therapeutic pathway in cHL. In this review, we will summarize recent findings on cHL biology and novel treatment options clinically available, as well as promising future perspectives in the field.

Bioinformatics Analysis Reveals Prognostic Significance of the Macrophage Marker Gene Signature in Gastric Adenocarcinoma.

Gastric adenocarcinoma (GAC) is a malignant tumor with the highest incidence in the digestive system. Macrophages have been proven to play important roles in tumor microenvironment. Herein, single-cell RNA sequencing (scRNA-seq) profiles from the Gene Expression Omnibus (GEO) and bulk RNA-seq data from the Cancer Genome Atlas (TCGA) database were utilized to construct a macrophage marker gene signature (MMGS) to predict the prognosis of GAC patients. Subsequently, a risk score model based on the MMGS was built to predict the prognosis of GAC patients; further, this was validated in the GEO cohort. The risk score categorized patients into the high- and low-risk groups. A nomogram model based on the risk score and clinic-pathological characteristics was developed. Seven genes, ABCA1, CTHRC1, GADD45B, NPC2, PLTP, PRSS23, and RNASE1, were included in the risk score model. Patients with a low-risk score showed a better prognosis. The MMGS had good sensitivity and specificity for predicting the prognosis inGAC patients. The risk score was an independent prognostic factor. The constructed nomogram exhibited favorable predictability and reliability for predicting GAC prognosis. In conclusion, the risk score model based on the seven MMGSs performed well in the predicting prognosis of GAC patients. Our study may provide new insights into clinical decision-making for the personalized treatment of patients with gastric cancer (GC).

Tumor-Associated Senescent Macrophages, Their Markers, and Their Role in Tumor Microenvironment.

Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and the most abundant population of immune cells infiltrating a tumor. TAMs can largely determine direction of anti-tumor immune response by promoting it or, conversely, contribute to formation of an immunosuppressive TME that allows tumors to evade immune control. Through interactions with tumor cells or other cells in the microenvironment and, as a result of action of anti-cancer therapy, macrophages can enter senescence. In this review, we have attempted to summarize information available in the literature on the role of senescent macrophages in tumors. With the recent development of senolytic therapeutic strategies aimed at removing senescent cells from an organism, it seems important to discuss functions of the senescent macrophages and potential role of the senolytic drugs in reprogramming TAMs to enhance anti-tumor immune response and improve efficacy of cancer treatment.

Stromal B Lymphocytes Affecting Prognosis in Triple-Negative Breast Cancer by Opal/TSA Multiplexed Immunofluorescence.

Immune cells play a key role in tumor microenvironment. The purpose of this study was to investigate the infiltration and clinical indication of immune cells including their combined prognostic value in microenvironment of triple negative breast cancer. We investigated 100 patients with triple negative breast cancer by Opal/Tyramide Signal Amplification multispectral immunofluorescence between 2003 and 2017 at Zhejiang Provincial people's Hospital. Intratumoral and stromal immune cells of triple negative breast cancer were classified and quantitatively analyzed. Survival outcomes were compared using the Kaplan-Meier method and further analyzed with multivariate analysis. Infiltration level of stromal B lymphocytes, stromal and intratumoral CD8+ T cells, stromal CD4+ T cells, stromal PD-L1 and intratumoral tumor associated macrophages 2 cells were shown as independent factors affecting disease-free survival and overall survival in univariate analysis. Stromal B lymphocytes, T stage, N stage and pathological type were independent predictive factors for both DFS and OS in multivariate analysis. We firstly found that patients with B lymphocytes-enriched subtypes have a better prognosis than those with T lymphocytes-enriched subtypes and tumor-associated macrophage-enriched subtypes. The present study identified a bunch of immune targets and subtypes, which could be exploited in future combined immunotherapy/chemotherapy strategies for triple negative breast cancer patients.

Abstract 1086: ZFP36L2 is expected to be a potential prognostic marker in IL-1β+ osteosarcoma patients

Abstract Background: Osteosarcoma (OS) is the most common bone malignancy affect children and young adults. For decades, the long-term survival for patients with recurrences and metastases remains ~30%. There’s an urgent need for new prognostic marker and therapeutic options. ZFP36L2, a member of the tristetraprolin (TTP) family of CCCH zinc finger proteins, stands out for its pivotal role in post transcriptional modifications and modify tumor microenvironment (TME). Notably, ZFP36L2 contributes to the recruitment of macrophages, specifically the M1 subtype, which are known for their ability to secrete IL1β and exhibit anti-tumor functions. Our study reveals that, ZFP36L2 can be used as a predictor of prognosis in OS patients with enriched IL1B expression. This study aims to elucidate the interaction between ZFP36L2 and IL1B in modification of TME and shed light on its potential of prognosis prediction and therapeutic in IL1β positive OS patients. Methods: Firstly, we conducted a comprehensive exploration of ZFP36L2 expression across TCGA cohorts. Then, we performed IHC staining to confirm the evaluated expression of ZFP36L2 in cancerous tissues. Immune infiltration analysis, including QUANTISEQ, TIMER, and CIBERSORT, was conducted. KM plot was employed to analyze the prognosis of OS patients. Finally, qPCR and western blot were used to validate transcriptional and translational changes of key molecules across OS cell lines. Results: Our findings demonstrate that ZFP36L2 exhibits specific expression across various cancer types, with a notable elevation in sarcoma tissues, as confirmed by IHC. Importantly, this high expression of ZFP36L2 in sarcoma tissues is correlated with metastasis. We found ZFP36L2 significantly correlates with tumor metastasis but failed in patient overall survival. Immunoinfiltration analysis indicates a significant correlation between ZFP36L2 and macrophages, as well as T cells, suggesting a role in the TME. Prognostic analysis reveals that ZFP36L2 can serve as a predictive marker for IL1β positive patients. The wetlab experiments demonstrated that ZFP36L2 leads to IRGM mRNA degradation, ultimately affecting IL1β+ macrophages. Conclusion: This study delineates the tumor-specific elevated expression of ZFP36L2 and its potential as a prognostic marker in IL1β+ OS patients. We hypothesize that ZFP36L2 affects IL1β+ macrophages through IRGM degradation. Besides, IRGM also has an impact on cytotoxic T cells. Therefore, the ZFP36L2-IRGM axis plays an important role in remodeling OS TME. These results indicated ZFP36L2, not only serves as a marker, but also can be a therapeutic target in IL1β enriched patients. Citation Format: Peiyao Hao, Piaopiao Luo, Zhenhua Ren, Shenglin Xu, Jijun Han, Xiang Nan. ZFP36L2 is expected to be a potential prognostic marker in IL-1β+ osteosarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1086.

Abstract 3919: Targeting tissue-resident macrophage progenitors by anti-IL34 restores anti-tumor immunity and suppresses tumor growth

Abstract Macrophages play important roles in tumor microenvironment, where they can promote immune suppression, tumor growth and resistance to checkpoint inhibitor therapy and are the focus of efforts to develop novel cancer therapeutics. Strategies to inhibit macrophage accumulation to suppress tumor growth by blocking their recruitment from circulation have been only partially effective, leading to the identification of roles in tumor progression for tissue resident macrophages that are seeded during embryonic development. We examined the origins of lung tumor associated macrophages using lineage tracing, flow cytometry, and single cell sequencing. By comparing gene expression profiles of resident F4/80hi Lyve1+ Ly6C- macrophages and Ly6C+ F4/80lo CCR2+ recruited macrophages in subcutaneous, lung, central nervous and renal normal and tumor tissues, we identified generic tissue resident macrophage and recruited macrophage transcriptomic signatures, revealing that resident macrophages are characterized by signatures of Myc driven proliferation, fatty acid and cholesterol metabolism and immune suppression, while recruited macrophages are characterized by signature of inflammation and immune stimulation. Resident macrophages were associated with worse outcomes in cancer patients than recruited macrophages. Single cell sequencing and flow cytometry of genetically engineered mouse models of CC10-Cre KrasG12D;p53-/- and SPC-Cre KrasG12D lung cancer revealed that lung tumor progression was characterized by extensive expansion of immune suppressive, Ki67+ resident alveolar macrophages and loss of T cells in the lung. Single cell transcriptomics identified IL-34 expressed exclusively by tumor cells as a possible driver of alveolar macrophage proliferation and IGF1 expressed by tumor associated alveolar macrophages as a possible regulator of tumor cell proliferation. Accordingly, blockade of IL-34 profoundly reduced tissue resident macrophage proliferation, stimulated recruitment of activated T cells, and suppressed growth of KrasG12D driven tumors. Analysis of TCGA data sets revealed that expression of IGF1 or IL34 was associated with reduced survival in lung, kidney, liver, head and neck and ovarian cancer. These studies identify key roles for IL-34 and IGF1 in solid tumor progression and suggest new therapeutic targets for the development of therapeutic strategies to stimulate anti-cancer immunity. Citation Format: Hui Chen, Jaroslav Zak, Mark Paradise, Guangfang Wang, John Teijaro, Mark Onaitis, Judith Varner. Targeting tissue-resident macrophage progenitors by anti-IL34 restores anti-tumor immunity and suppresses tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3919.