Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3 -mutated urothelial carcinoma and FGFR2 -fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.

According to the established model of murine innate lymphoid cell (ILC) development, helper ILCs develop separately from natural killer (NK) cells. However, it is unclear how helper ILCs and NK cells develop in humans. Here we elucidated key steps of NK cell, ILC2, and ILC3 development within human tonsils using ex vivo molecular and functional profiling and lineage differentiation assays. We demonstrated that while tonsillar NK cells, ILC2s, and ILC3s originated from a common CD34CD117 ILC precursor pool, final steps of ILC2 development deviated independently and became mutually exclusive from those of NK cells and ILC3s, whose developmental pathways overlapped. Moreover, we identified a CD34CD117 ILC precursor population that expressed CD56 and gave rise to NK cells and ILC3s but not to ILC2s. These data support a model of human ILC development distinct from the mouse, whereby human NK cells and ILC3s share a common developmental pathway separate from ILC2s.

Acute myeloid leukemia (AML) can evade the mouse and human innate immune system by suppressing natural killer (NK) cell development and NK cell function. This is driven in part by the overexpression of microRNA (miR)-29b in the NK cells of AML patients, but how this occurs is unknown. In the current study, we demonstrate that the transcription factor aryl hydrocarbon receptor (AHR) directly regulates miR-29b expression. We show that human AML blasts activate the AHR pathway and induce miR-29b expression in NK cells, thereby impairing NK cell maturation and NK cell function, which can be reversed by treating NK cells with an AHR antagonist. Finally, we show that inhibition of constitutive AHR activation in AML blasts lowers their threshold for apoptosis and decreases their resistance to NK cell cytotoxicity. Together, these results identify the AHR pathway as a molecular mechanism by which AML impairs NK cell development and function. The results lay the groundwork in establishing AHR antagonists as potential therapeutic agents for clinical development in the treatment of AML.

3620 Background: Activating genomic alterations (GAs) in the fibroblast growth factor receptor (FGFR) gene family occur in many tumor types. FGFR1-3 mutations and rearrangements are of particular interest given evidence of clinical activity of selective FGFR inhibitors in patients (pts) with susceptible alterations. We queried FGFR1-3 GAs in patient tumor samples analyzed using comprehensive genomic profiling (CGP) and performed in vitro characterization of select novel alterations. Methods: Tumor samples were assayed by hybrid capture based CGP on 0.8-1.2 Mb of the genome to identify GAs in exons and select introns in up to 404 genes (Foundation Medicine, Inc, Cambridge MA). Cell lines were stably transduced with alterations of interest and transformation assays and drug sensitivity assays were performed to determine oncogenic potential and sensitivity to FGFR inhibition by pemigatinib. Results: GAs in FGFR1-3 were present in 6314 of 274,694 pt specimens (2.3%), of which 4091 (64.8%) were short variants and 2269 (35.9%) were rearrangements. Tumor types with the highest frequency of FGFR1-3 alterations were bladder cancer (17.9%), cholangiocarcinoma (11.1%), endometrial cancer (7.9%), and glioma (5.5%) (Table). We identified 270 unique FGFR1-3 short-variants, including 144 missense mutations and 94 truncating alterations. Of short variants, the most frequent were FGFR3 p.S249C (18.3%), FGFR2 p.S252W (9.9%) and FGFR1 p.N546K (6.9%). Truncating alterations were largely identified in exon 18, downstream of the kinase domain. We identified 476 unique FGFR1-3 rearrangement pairs ( FGFR1; n=77, FGFR2; n=338, FGFR3; n=61). FGFR3-TACC3 was the most prevalent FGFR rearrangement (29.0%), followed by FGFR2-BICC1 and FGFR2-N/A (both 9.7%). In vitro analysis of the transforming potential and drug sensitivity for select alterations will be reported. Conclusions: FGFR1-3 mutations and rearrangements are highly diverse and present at low to moderate frequencies across many cancers. Therefore, cataloging and characterizing these diverse alterations has the potential to facilitate precision medicine. Tumor-specific and -agnostic trials of selective FGFR inhibitors in pts with susceptible alterations are ongoing. [Table: see text]