ABSTRACT
Fungal plasma membrane proteins represent key therapeutic targets for antifungal agents, yet their structure and spatial distribution in the native context remain poorly characterized. Herein, we employ an integrative multimodal approach to elucidate the structural and functional organization of plasma membrane protein complexes in Candida glabrata , focusing on prominent and essential membrane proteins, the polysaccharide synthase ß-(1,3)-glucan synthase (GS) and the proton pump Pma1. Cryo-electron tomography (cryo-ET) and live cell imaging reveal that GS and Pma1 are heterogeneously distributed into distinct plasma membrane microdomains. Treatment with caspofungin, an echinocandin antifungal that targets GS, alters the plasma membrane and disrupts the native distribution of GS and Pma1. Based on these findings, we propose a model for echinocandin action that considers how drug interactions with the plasma membrane environment lead to inhibition of GS. Our work underscores the importance of interrogating the structural and dynamic characteristics of fungal plasma membrane proteins in situ to understand function and facilitate precisely targeted development of novel antifungal therapies.
ABSTRACT
Antigen-presenting cells (APCs) are pivotal mediators of immune responses. Their role has increasingly been spotlighted in the realm of cancer immunology, particularly as our understanding of immunotherapy continues to evolve and improve. There is growing evidence that these cells play a non-trivial role in cancer immunity and have roles dependent on surface markers, growth factors, transcription factors, and their surrounding environment. The main dendritic cell (DC) subsets found in cancer are conventional DCs (cDC1 and cDC2), monocyte-derived DCs (moDC), plasmacytoid DCs (pDC), and mature and regulatory DCs (mregDC). The notable subsets of monocytes and macrophages include classical and non-classical monocytes, macrophages, which demonstrate a continuum from a pro-inflammatory (M1) phenotype to an anti-inflammatory (M2) phenotype, and tumor-associated macrophages (TAMs). Despite their classification in the same cell type, each subset may take on an immune-activating or immunosuppressive phenotype, shaped by factors in the tumor microenvironment (TME). In this review, we introduce the role of DCs, monocytes, and macrophages and recent studies investigating them in the cancer immunity context. Additionally, we review how certain characteristics such as abundance, surface markers, and indirect or direct signaling pathways of DCs and macrophages may influence tumor response to immune checkpoint blockade (ICB) therapy. We also highlight existing knowledge gaps regarding the precise contributions of different myeloid cell subsets in influencing the response to ICB therapy. These findings provide a summary of our current understanding of myeloid cells in mediating cancer immunity and ICB and offer insight into alternative or combination therapies that may enhance the success of ICB in cancers.
ABSTRACT
Cancer is a disease that undergoes selective pressure to evolve during its progression, becoming increasingly heterogeneous. Tumoral heterogeneity can dictate therapeutic response. Transcriptomics can be used to uncover complexities in cancer and reveal phenotypic heterogeneity that affects disease response. This is especially pertinent in the immune microenvironment, which contains diverse populations of immune cells, and whose dynamic properties influence disease response. The recent development of immunotherapies has revolutionized cancer therapy, with response rates of up to 50% within certain cancers. However, despite advances in immune checkpoint blockade specifically, there remains a significant population of non-responders to these treatments. Transcriptomics can be used to profile immune and other cell populations following immune-checkpoint inhibitor (ICI) treatment, generate predictive biomarkers of resistance or response, assess immune effector function, and identify potential immune checkpoints. Single-cell RNA sequencing has offered insight into mRNA expression within the complex and heterogeneous tumor microenvironment at single-cell resolution. Spatial transcriptomics has enabled measurement of mRNA expression while adding locational context. Here, we review single-cell sequencing and spatial transcriptomic research investigating ICI response within a variety of cancer microenvironments.
