Browsing by Subject "Cancer immunology"

Now showing 1 - 3 of 3
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    ARF6 is a Novel Target for Immunotherapy in Triple Negative Breast Cancer
    (2024-07) Moulana, Fathima Ishara; Lu, Xiongbin; Pollok, Karen; Hopewell, Emily; Liu, Jing
    Triple negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes with poor clinical outcomes due to lack of effective treatments owing to its hormone receptor negative status. Immune checkpoint blockade (ICB) therapy, which prevents the exhaustion of CD8+ T cells, has shown promise in treating these patients. However, only a small proportion respond, possibly due to resistance and immune evasion mechanisms by the tumor cells. A primary mechanism by which tumor cells evade immune surveillance is by reduced tumor antigen presentation, as indicated by a decreased level of antigen-MHC-I (major histocompatibility complex-I) on the surface of tumor cells. The dynamics of tumor antigens on the cell surface and how cell endocytosis contributes to antigen presentation and their recycling is little known. Here we sought to study the roles of two proteins: clathrin and ADP-Ribosylation Factor 6 (ARF6) which are essential for clathrin-mediated endocytosis and clathrin-independent endocytosis respectively, on the surface turnover of fluorophore-conjugated antigenic peptide bound to MHC-I. We employed Total Internal Reflection Fluorescence Microscopy (TIRFM) and Single Molecule Tracking (SMT) to determine the dynamics of tumor antigen endocytosis on the surface of EO771 murine TNBC cells. We found that the inhibition of ARF6 remarkably impaired the endocytosis of the antigen-MHC-I foci, leading to extended stay of the foci on the cell membrane, while inhibition of clathrin did not, suggesting that clathrin-independent endocytosis is the primary route for MHC-I-mediated antigen endocytosis. Consistent with this finding, reduced ARF6 levels promoted in vitro tumor cell killing by CD8+ T cells and suppressed tumor growth in mice when combined with ICB therapy. We further investigated the effect of pharmacological inhibition of ARF6 in murine TNBC cells and splenic CD8+ T cells using a commercially available ARF6 inhibitor NAV-2729. Treatment with NAV-2729 increased surface MHC-I levels and enhanced the secretion of T cell functional markers such as IFN-, TNF- and IL-2, suggesting the possibility of in vivo administration of ARF6 inhibitors in combination with ICB therapy. Collectively, these data suggest that ARF6 is a novel target for the combined treatment with ICB therapy to improve its efficacy in TNBC patients.
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    CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10
    (Cell Press, 2020) Guldner, Ian H.; Wang, Qingfei; Yang, Lin; Golomb, Samantha M.; Zhao, Zhuo; Lopez, Jacqueline A.; Brunory, Abigail; Howe, Erin N.; Zhang, Yizhe; Palakurthi, Bhavana; Barron, Martin; Gao, Hongyu; Xuei, Xiaoling; Liu, Yunlong; Li, Jun; Chen, Danny Z.; Landreth, Gary E.; Zhang, Siyuan; Medical and Molecular Genetics, School of Medicine
    Brain metastasis (br-met) develops in an immunologically unique br-met niche. Central nervous system-native myeloid cells (CNS-myeloids) and bone-marrow-derived myeloid cells (BMDMs) cooperatively regulate brain immunity. The phenotypic heterogeneity and specific roles of these myeloid subsets in shaping the br-met niche to regulate br-met outgrowth have not been fully revealed. Applying multimodal single-cell analyses, we elucidated a heterogeneous but spatially defined CNS-myeloid response during br-met outgrowth. We found Ccr2+ BMDMs minimally influenced br-met while CNS-myeloid promoted br-met outgrowth. Additionally, br-met-associated CNS-myeloid exhibited downregulation of Cx3cr1. Cx3cr1 knockout in CNS-myeloid increased br-met incidence, leading to an enriched interferon response signature and Cxcl10 upregulation. Significantly, neutralization of Cxcl10 reduced br-met, while rCxcl10 increased br-met and recruited VISTAHi PD-L1+ CNS-myeloid to br-met lesions. Inhibiting VISTA- and PD-L1-signaling relieved immune suppression and reduced br-met burden. Our results demonstrate that loss of Cx3cr1 in CNS-myeloid triggers a Cxcl10-mediated vicious cycle, cultivating a br-met-promoting, immune-suppressive niche.
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    The Evolving Role of CD8+CD28- Immunosenescent T Cells in Cancer Immunology
    (MDPI, 2019-06-08) Huff, Wei X.; Kwon, Jae Hyun; Henriquez, Mario; Fetcko, Kaleigh; Dey, Mahua; Neurosurgery, IU School of Medicine
    Functional, tumor-specific CD8+ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8+ effector T cell dysfunction. Among the many facets of CD8+ T cell dysfunction that have been recognized-tolerance, anergy, exhaustion, and senescence-CD8+ T cell senescence is incompletely understood. Naïve CD8+ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8+CD28- senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8+CD28- senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8+ T cells could improve the efficacy of future anti-tumor immunotherapy.