SUMMARY Greater than 85% of advanced breast cancer patients suffer from metastatic bone lesions yet the mechanisms that facilitate these metastases remain poorly understood. Recent studies suggest that tumor-derived factors initiate changes within the tumor microenvironment to facilitate metastasis. However, whether stromal-initiated changes are sufficient to drive increased metastasis in the bone remains an open question. Thus, we developed a model to induce reactive senescent osteoblasts and found that they increased breast cancer colonization of the bone. Analysis of senescent osteoblasts revealed that they failed to mineralize bone matrix, and increased local osteoclastogenesis; the latter process being driven by the senescence-associated secretory phenotype factor, IL-6. Neutralization of IL-6 was sufficient to limit senescence-induced osteoclastogenesis and tumor cell localization to bone, thereby reducing tumor burden. Together, these data suggest that a reactive stromal compartment can condition the niche, in the absence of tumor-derived signals, to facilitate metastatic tumor growth in the bone.
Summary The multi-domain scaffolding protein Scribble (Scrib) organizes key signaling complexes to specify basolateral cell polarity and suppress aberrant growth. In many human cancers, genetically normal Scrib mislocalizes from cell–cell junctions to the cytosol, correlating with enhanced growth signaling and malignancy. Here we confirm that expression of the epithelial-to-mesenchymal transcription factor (EMT-TF) Snail in benign epithelial cells leads to Scrib displacement from the plasma membrane, mimicking the mislocalization observed in aggressive cancers. Upon further examination, Snail promotes a transcriptional program that targets genes in the palmitoylation cycle, repressing many protein acyl transferases and elevating expression and activity of protein acyl thioesterase 2 (APT2). APT2 isoform-selective inhibition or knockdown rescued Scrib membrane localization and palmitoylation while attenuating MEK activation. Overall, inhibiting APT2 restores balance to the Scrib palmitoylation cycle, promoting membrane re-localization and growth attenuation. These findings emphasize the importance of S-palmitoylation as a post-translational gatekeeper of cell polarity-mediated tumor suppression.
IMPORTANCE Better biomarkers are needed for human papillomavirus (HPV)-negative oropharyngeal cancer (OPC) to identify patients at risk of recurrence. Lymphopenia and an elevated ratio of neutrophils to lymphocytes (NLR) have been associated with poor disease outcomes in a number of solid tumors. OBJECTIVE To test the hypothesis that postradiotherapy lymphopenia and elevated NLR are associated with poor clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS This single-institution retrospective analysis included patients with HPV-negative OPC treated from January 1, 1997, through January 4, 2017. Median follow-up was 37 months (range, 2-197 months). A total of 108 patients with HPV-negative OPC and at least 1 complete blood cell count 2 to 12 months after the start of radiotherapy were included. Data were analyzed from August 26 to September 7, 2017. INTERVENTIONS Surgery followed by radiotherapy vs definitive radiotherapy, with or without chemotherapy. MAIN OUTCOMES AND MEASURES Absolute lymphocyte (ALC) and absolute neutrophil (ANC) counts were tested as variables affecting locoregional control, recurrence-free survival, and overall survival. RESULTS Of a total of 108 patients included in the analysis (87.0% male; mean age, 56 years [range, 35-84 years]), 57 received surgery followed by postoperative radiotherapy and 51 received definitive radiotherapy. During treatment, 67 of 79 patients (84.8%) had grades 3 to 4 lymphopenia and 17 of 79 (21.5%) had grade 4 lymphopenia. The ANC recovered by 6 months after radiotherapy, but ALC remained depressed to 1 year after radiotherapy. Posttreatment lymphopenia and elevated NLR were associated with worse recurrence-free and overall survival. The estimated 3-year LRC in patients with and without grades 3 to 4 lymphopenia at 3 months after radiotherapy start was 73% vs 82% (hazard ratio [HR], 0.58; 95% CI, 0.19-1.8); estimated 3-year recurrence-free survival, 36% vs 63% (HR, 0.45; 95% CI, 0.23-0.87); and estimated 3-year overall survival, 34% vs 64% (HR, 0.45; 95% CI, 0.23-0.88). In multivariable analysis, an association with worse overall survival was found for definitive radiotherapy (HR, 3.3; 95% CI, 1.6-7.1) and grades 3 to 4 lymphopenia (HR, 2.6; 95% CI, 1.3-5.5) at 3 months after radiotherapy. CONCLUSIONS AND RELEVANCE Lymphopenia and NLR as early as 3 months after treatment start may serve as biomarkers of clinical outcomes in patients with HPV-negative OPC. These patients may benefit from adjuvant treatment intensification or closer surveillance.
Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA -haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on day +7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in a clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well tolerated, and 87% of patients achieved a composite complete response at day +28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for 2 months after HCT with 1104-fold expansion (over 1 to 2 weeks). Phenotypic and transcriptional analyses identified donor ML NK cells as distinct from conventional NK cells and showed that ML NK cells persisted for over 2 months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patients and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML.
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