Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their ...abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.
Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; ...Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib's efficacy in breast cancer models. Nine breast cancer patient-derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2-amplified model and prolonged regression (> 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%-2.6% and 1.5%-2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.
In this work, we leverage graphene’s unique tunable Seebeck coefficient for the demonstration of a graphene-based thermal imaging system. By integrating graphene based photothermo-electric detectors ...with micromachined silicon nitride membranes, we are able to achieve room temperature responsivities on the order of ∼7–9 V/W (at λ = 10.6 μm), with a time constant of ∼23 ms. The large responsivities, due to the combination of thermal isolation and broadband infrared absorption from the underlying SiN membrane, have enabled detection as well as stand-off imaging of an incoherent blackbody target (300–500 K). By comparing the fundamental achievable performance of these graphene-based thermopiles with standard thermocouple materials, we extrapolate that graphene’s high carrier mobility can enable improved performances with respect to two main figures of merit for infrared detectors: detectivity (>8 × 108 cm Hz1/2 W–1) and noise equivalent temperature difference (<100 mK). Furthermore, even average graphene carrier mobility (<1000 cm2 V–1 s–1) is still sufficient to detect the emitted thermal radiation from a human target.
High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity ...and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents - cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR - in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.
Fluorine-18 (18F)-fluorodeoxyglucose (FDG) positron emission tomography fused with computed tomography (PET/CT) is a valuable tool in surgical planning for head and neck squamous cell carcinoma ...(HNSCC). If performed prior to biopsy or other surgical intervention, FDG-PET/CT has high sensitivity for the detection of the primary site in patients with cervical lymph node metastases from unknown primary origin and can be used to direct the surgical workup. FDG-PET/CT is superior to CT alone for detection of nodal metastases outside the expected pattern or distant metastases or second primary cancers and can greatly affect determination of appropriate management including surgical eligibility. Prior to the advent of PET/CT, many patients undergoing (chemo)radiation-based therapy had planned post-treatment neck dissection; FDG-PET/CT now has a proven role in the evaluation of recurrent or persistent disease amenable to salvage surgery and enables safe avoidance of planned postradiation neck dissection with a high negative predictive value. Specifically for this important application, two standardized reporting metrics may be used in the head and neck anatomic region: the “Hopkins criteria” and the “Neck Imaging Reporting and Data System”; both systems produce a formalized evaluation and recommendation based on PET/CT findings. The role of PET/CT as a replacement for elective neck dissection or examination under anesthesia remains controversial but deserves further study. FDG-PET/CT has a wide-ranging impact on the surgical management of patients with HNSCC and should be used routinely in patients with unknown primary nodal disease and those presenting with advanced-stage cancers at initial staging and to assess treatment response.
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