Robert L. Witt

ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R–mediated apoptosis

Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis-induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs.

Facial nerve function after partial superficial parotidectomy: An 11-year review (1987-1997).

Permanent facial nerve dysfunction is a potential complication of every parotid surgery. Partial superficial parotidectomy, a conservative resectioning that requires neither dissection of the full facial nerve nor excision of the superficial lobe, produces lower rates of facial nerve dysfunction and soft tissue deformity than the traditional method. This report describes a single surgeons experience with partial superficial parotidectomy from 1987 to 1997. Fifty-nine patients with mobile, benign, and low-grade malignant tumors, limited to the superficial lobe, underwent partial superficial parotidectomy with selective nerve dissection. Adequate margins were obtained, based on the premise that the tumor-to-nerve margin is often the true one. No patients had permanent nerve paralysis or paresis, and only 10 incurred transient facial nerve paresis. Age, histology, and sex were not significant factors in postoperative facial nerve function. No patients had recurrences.

Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients

PMN-MDSC in cancer patients can be distinguished from neutrophils by a genomic signature and by expression of the LOX-1 receptor. Stressing myeloid-derived suppressor cells in cancer Immunotherapies for cancer have shown promising results in part because they overcome the suppressive effects of the tumor microenvironment on immune cells. Condamine et al. now report that polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) can be distinguished from neutrophils in the same cancer patient by the expression of the lipid metabolism–related molecule lectin-type oxidized LDL receptor-1 (LOX-1). LOX-1–expressing neutrophils were nearly undetectable in healthy individuals but were found prominently in tumor tissues. Moreover, exposing neutrophils from healthy individuals to endoplasmic reticulum stress resulted in up-regulation of LOX-1 and increased suppressive function. These data support the specific targeting of LOX-1–expressing PMN-MDSC for cancer immunotherapy. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are important regulators of immune responses in cancer and have been directly implicated in the promotion of tumor progression. However, the heterogeneity of these cells and the lack of distinct markers hamper the progress in understanding the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation, we determined that low-density PMN-MDSC and high-density neutrophils from the same cancer patients had a distinct gene profile. The most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Unexpectedly, low-density lipoprotein (LDL) was one of the most increased regulators, and its receptor oxidized LDL receptor 1 (OLR1) was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor-1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5 to 15% of total neutrophils in cancer patients and 15 to 50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1− counterparts, LOX-1+ neutrophils had gene signature, potent immunosuppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSCs. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSCs. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insights into the biology and potential therapeutic targeting of these cells.

Combined KIT and FGFR2b signaling regulates epithelial progenitor expansion during organogenesis.

Summary Organ formation and regeneration require epithelial progenitor expansion to engineer, maintain, and repair the branched tissue architecture. Identifying the mechanisms that control progenitor expansion will inform therapeutic organ (re)generation. Here, we discover that combined KIT and fibroblast growth factor receptor 2b (FGFR2b) signaling specifically increases distal progenitor expansion during salivary gland organogenesis. FGFR2b signaling upregulates the epithelial KIT pathway so that combined KIT/FGFR2b signaling, via separate AKT and mitogen-activated protein kinase (MAPK) pathways, amplifies FGFR2b-dependent transcription. Combined KIT/FGFR2b signaling selectively expands the number of KIT+K14+SOX10+ distal progenitors, and a genetic loss of KIT signaling depletes the distal progenitors but also unexpectedly depletes the K5+ proximal progenitors. This occurs because the distal progenitors produce neurotrophic factors that support gland innervation, which maintains the proximal progenitors. Furthermore, a rare population of KIT+FGFR2b+ cells is present in adult glands, in which KIT signaling also regulates epithelial-neuronal communication during homeostasis. Our findings provide a framework to direct regeneration of branched epithelial organs.

The incidence and management of siaolocele after parotidectomy

Objectives: (1) To determine if a postparotidectomy sialocele occurs at a higher incidence with a partial superficial parotidectomy compared with a near-complete parotidectomy and (2) to determine if needle aspiration versus observation yield more persistent sialoceles beyond 1 month. Study Design: A single-surgeon, single-institution case series with a chart review. Methods: Comparing 100 consecutive partial superficial parotidectomy procedures and 20 consecutive near-total parotidectomy procedures for formation of a postoperative sialocele. Patients were evaluated at 1 week and 1 month postoperatively. The first 18 sialoceles were treated with one or more needle aspirations. The last 21 sialoceles were treated with observation. Results: There were 39 sialoceles in the partial superficial parotidectomy group (39/100, 39%) and none in the near-total parotidectomy group (0/20, 0%) (P < 0.05). All sialoceles resolved by the end of the first postoperative month whether aspirated or not aspirated. Conclusions: Sialoceles are common postpartial superficial parotidectomy, and they did not occur after near-total parotidectomy. Sialoceles can generally be treated by observation with an expectation of resolution within 1 month.

Initial Surgical Management of Thyroid Cancer

The rapid increase in the rate of papillary thyroid cancer is likely caused by improved surveillance. A significant trend toward total thyroidectomy for low-risk differentiated thyroid cancer is present in the United States after a paradigm shift from treatment of macroscopic disease to the treatment of macroscopic and microscopic disease by increasingly sensitive tests. Compelling arguments for thyroid lobectomy and total thyroidectomy for low-risk thyroid cancer remain. The relatively small number of deaths from thyroid cancer, the small number of clinical thyroid cancers, and the huge number of incidental thyroid cancers are indicative of how little we understand the biology of this disease. Clinical medicine awaits biologic markers to refine treatment recommendations.

Major salivary gland cancer

Major salivary gland cancers are rare, with many histologic types and subtypes. The tumor stage at presentation will dictate the need for imaging,FNA, and facial nerve monitoring. Immunohistochemistry has enhanced diagnosis. In addition, precise attention to surgical landmarks and technique will reduce complications. Tumor stage, histologic type, tumor grade,surgical margin, facial nerve dysfunction, perineural involvement, extra-parenchymal spread, and nodal metastasis are factors influencing the indication for neck dissection, postoperative radiation therapy, and survival rate.

Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using DS-8273a, an Agonistic TRAIL-R2 Antibody

Purpose: Myeloid-derived suppressor cells (MDSC) are one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSCs. Experimental Design: The TRAIL-R2 agonistic antibody (DS-8273a) has been tested in 16 patients with advanced cancers enrolled in a phase I trial. The antibody (24 mg/kg) was administered intravenously once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated. Results: The treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Treatment with DS-8273a resulted in reduction of the elevated numbers of MDSCs in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSCs rebounded back to the pretreatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells. Decrease in MDSCs inversely correlated with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSCs in 50% of the patients who were able to provide pre- and on-treatment biopsies. Conclusions: Targeting TRAIL-R2 resulted in elimination of different populations of MDSCs without affecting mature myeloid or lymphoid cells. These data support the use of this antibody in combination immmunotherapy of cancer. Clin Cancer Res; 23(12); 2942–50. ©2016 AACR.

A Novel In Vivo Model for Evaluating Functional Restoration of a Tissue-Engineered Salivary Gland

To create a novel model for development of a tissue‐engineered salivary gland from human salivary gland cells that retains progenitor cell markers useful for treatment of radiation‐induced xerostomia.

Sarcoidosis Presenting as Bilateral Vocal Fold Paralysis

Sarcoidosis with cranial polyneuritis and mediastinal granulomatous compression as a cause of unilateral left vocal fold paralysis has been reported infrequently. No case of sarcoidosis causing bilateral vocal fold paralysis in the abducted position has been reported in the Otolaryngology/Voice literature. Vocal fold function can be impacted in sarcoidosis by direct laryngeal involvement or by neural pathways. In the patient described in this case, sarcoid cranial polyneuritis coupled with bilateral paratracheal and mediastinal adenopathy resulted in bilateral vocal fold paralysis. This patient had a dramatic response to treatment with steroids. Sarcoidosis should be included in the differential diagnosis of unilateral or bilateral vocal fold paralysis.