Project description:Drug resistance to approved systemic therapies in estrogen receptor-positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance. FGF2-driven drug resistance in anti-estrogen-sensitive and -resistant models, including patient-derived xenografts, was reverted by neutralizing FGF2 or FGFRs. A transcriptomic signature of FGF2 signaling in primary tumors predicted shorter recurrence-free survival independently of age, grade, stage, and FGFR amplification status. These findings delineate FGF2 signaling as a ligand-based drug resistance mechanism and highlights an underdeveloped aspect of precision oncology: characterizing and treating patients according to their TME constitution.
Project description:Triple-negative breast cancer (TNBC) is a subtype of breast cancer known for its high aggressiveness and poor prognosis. Conventional treatment of TNBC is challenging due to its heterogeneity and lack of clear targets. Recent advancements in immunotherapy have shown promise in treating TNBC, with immune checkpoint therapy playing a significant role in comprehensive treatment plans. The tumor microenvironment (TME), comprising immune cells, stromal cells, and various cytokines, plays a crucial role in TNBC progression and response to immunotherapy. The high presence of tumor-infiltrating lymphocytes and immune checkpoint proteins in TNBC indicates the potential of immunotherapeutic strategies. However, the complexity of the TME, while offering therapeutic targets, requires further exploration of its multiple roles in immunotherapy. In this review, we discuss the interaction mechanism between TME and TNBC immunotherapy based on the characteristics and composition of TME, and elaborate on and analyze the effect of TME on immunotherapy, the potential of TME as an immune target, and the ability of TME as a biomarker. Understanding these dynamics will offer new insights for enhancing therapeutic approaches and investigating stratification and prognostic markers for TNBC patients.
Project description:Heterogeneity of triple-negative breast cancer is well known at clinical, histopathological, and molecular levels. Genomic instability and greater mutation rates, which may result in the creation of neoantigens and enhanced immunogenicity, are additional characteristics of this breast cancer type. Clinical outcome is poor due to early age of onset, high metastatic potential, and increased likelihood of distant recurrence. Consequently, efforts to elucidate molecular mechanisms of breast cancer development, progression, and metastatic spread have been initiated to improve treatment options and improve outcomes for these patients. The extremely complex and heterogeneous tumor immune microenvironment is made up of several cell types and commonly possesses disorganized gene expression. Altered signaling pathways are mainly associated with mutated genes including p53, PIK3CA, and MAPK, and which are positively correlated with genes regulating immune response. Of note, particular immunity-associated genes could be used in prognostic indexes to assess the most effective management. Recent findings highlight the fact that long non-coding RNAs also play an important role in shaping tumor microenvironment formation, and can mediate tumor immune evasion. Identification of molecular signatures, through the use of multi-omics approaches, and effector pathways that drive early stages of the carcinogenic process are important steps in developing new strategies for targeted cancer treatment and prevention. Advances in immunotherapy by remodeling the host immune system to eradicate tumor cells have great promise to lead to novel therapeutic strategies. Current research is focused on combining immune checkpoint inhibition with chemotherapy, PARP inhibitors, cancer vaccines, or natural killer cell therapy. Targeted therapies may improve therapeutic response, eliminate therapeutic resistance, and improve overall patient survival. In the future, these evolving advancements should be implemented for personalized medicine and state-of-art management of cancer patients.
Project description:Immune checkpoint inhibitors (ICIs) targeting immune checkpoint proteins, such as CTLA-4 and PD-1/PD-L1, have demonstrated remarkable and durable clinical responses in various cancer types. However, a considerable number of patients receiving ICIs eventually experience a relapse due to diverse resistance mechanisms. As a result, there have been increasing research efforts to elucidate the molecular mechanisms behind resistance to ICIs and improve patient outcomes. There is growing evidence that the dysregulated metabolic activity of tumor cells generates an immunosuppressive tumor microenvironment (TME) that orchestrates an impaired anti-tumor immune response. Notably, the immunosuppressive TME is characterized by nutrient shortage, hypoxia, an acidic extracellular milieu, and abundant immunosuppressive molecules. A detailed understanding of the TME remains a major challenge in mounting a more effective anti-tumor immune response. Herein, we discuss how tumor cells reprogram metabolism to modulate a pro-tumor TME, driving disease progression and immune evasion; in particular, we highlight potential approaches to target metabolic vulnerabilities in the context of anti-tumor immunotherapy.
Project description:Immunotherapy is a major emerging treatment for breast cancer (BC). However, not all breast cancer patients derive benefit from immunotherapy. Predictive biomarkers of immunotherapy, such as tumor mutation burden and tumor-infiltrating lymphocytes, are promising to stratify the patients with BC and optimize the therapeutic effect. Various targets of the immune response pathway have also been explored to expand the modalities of immunotherapy. The use of nanotechnology for the imaging of predictive biomarkers and the combination with other therapeutic modalities presents a number of advantages for the immunotherapy of BC. In this review, we summary the emerging therapeutic modalities of immunotherapy, present prominent examples of immunotherapy in BC, and discuss the future opportunity of nanotechnology in the immunotherapy of BC.
Project description:Breast cancer has the highest global incidence among all cancers, affecting more than 2 million individuals annually. Despite the availability of new drugs and novel treatment combinations, it is postulated that the incidence and mortality of breast cancer will rise by 40.8% and 51.9% respectively by 2040. Such dire statistics are associated with the clonal evolution of cancer cells that leads to therapeutic resistance and consequent relapse in breast cancer patients. On the other hand, the tumor microenvironment (TME) comprising of tumor cells, cancer-associated immune cells, re-programmed stromal cells, and the extracellular matrix (ECM) creates an immunosuppressive niche facilitating immune evasion. This review focuses on a critical cellular component of the tumor microenvironment, the tumor-associated macrophages (TAMs) in breast cancer immunotherapy. Macrophages are inherently plastic and can convert from an anti-tumor M1 phenotype to a pro-tumor M2 phenotype based on microenvironmental cues. Cancer cells facilitate these cues, allowing the tumor-associated macrophages to gain M2 phenotype and mediate immune evasion. Therefore, knowledge of the distinct role of tumor-associated macrophages in immune evasion can help design therapeutics such as engineered macrophages, M2 targeting drugs, and novel macrophage-mediated drug delivery strategies for long-term survival in breast cancer.
Project description:Oral cancer is one of the most common malignant tumors of the head and neck, not only affects the appearance, but also affects eating and even endangers life. The clinical treatments of oral cancer mainly include surgery, radiotherapy, and chemotherapy. However, unsatisfactory therapeutic effect and toxic side effects are still the main problems in clinical treatment. Tumor microenvironment (TME) is not only closely related to the occurrence, growth, and metastasis of tumor but also works in the diagnosis, prevention, and treatment of tumor and prognosis. Future studies should continue to investigate the relationship of TME and oral cancer therapy. This purpose of this review was to analyze the characteristics of oral cancer microenvironment, summarize the traditional oral cancer therapy and immunotherapy strategies, and finally prospect the development prospects of oral cancer immunotherapy. Immunotherapy targeting tumor microenvironment is expected to provide a new strategy for clinical treatment of oral cancer.
Project description:Inflammatory breast cancer (IBC) is a rare and very aggressive subtype of breast cancer with clinical manifestations similar to acute inflammation. The prognosis of IBC is still poor even though combination therapy with surgery, chemotherapy, and target therapy, mainly due to a lack of fully understanding of the cellular and molecular mechanisms of IBC pathogenesis and progression. In the present article, we have comprehensively reviewed the connection of the pathogenesis of IBC and inflammation, immune reaction and cancer, particularly focused on the role and mechanism of tumor microenvironment related to IBC formation, tumor cell proliferation, migration, invasion and metastasis as well as the clinical manifestations of IBC. As the diverse cells including inflammatory cells, immune cells, and tumor cells and the soluble molecules produced by these cells in the microenvironment play an essential role in IBC development and progression. Therefore, anti-inflammatory therapy and immunotherapy with available agents warrant further investigation in the treatment of IBC.