Chemerin Suppresses Breast Cancer Growth by Recruiting Immune Effector Cells Into the Tumor Microenvironment

Infiltration of immune cells into the tumor microenvironment (TME) can regulate growth and survival of neoplastic cells, impacting tumorigenesis and tumor progression. Correlations between the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including breast, have been widely described. Current immunotherapies utilizing checkpoint inhibitors or co-stimulatory molecule agonists aim to activate effector immune cells. However, tumors often lack adequate effector cell numbers within the TME, resulting in suboptimal responses to these agents. Chemerin (RARRES2) is a leukocyte chemoattractant widely expressed in many tissues and is known to recruit innate leukocytes. CMKLR1 is a chemotactic cellular receptor for chemerin and is expressed on subsets of dendritic cells, NK cells, and macrophages. We have previously shown that chemerin acts as a tumor suppressive cytokine in mouse melanoma models by recruiting innate immune defenses into the TME. Chemerin/RARRES2 is down-regulated in many tumors, including breast, compared to normal tissue counterparts. Here, using a syngeneic orthotopic EMT6 breast carcinoma model, we show that forced overexpression of chemerin by tumor cells results in significant recruitment of NK cells and T cells within the TME. While chemerin secretion by EMT6 cells did not alter their phenotypic behavior in vitro, it did significantly suppress tumor growth in vivo. To define the cellular effectors required for this anti-tumor phenotype, we depleted NK cells or CD8+ T cells and found that either cell type is required for chemerin-dependent suppression of EMT6 tumor growth. Finally, we show significantly reduced levels of RARRES2 mRNA in human breast cancer samples compared to matched normal tissues. Thus, for the first time we have shown that increasing chemerin expression within the breast carcinoma TME can suppress growth by recruitment of NK and T cells, thereby supporting this approach as a promising immunotherapeutic strategy

Endonasal Access to the Upper Cervical Spine: Part 2—Cadaveric Analysis

Objectives The study aims to determine factors that augment endonasal exposure of the cervical spine. Setting We used fluoroscopy and endoscopy to study endonasal visualization of the upper cervical spine. Participants Ten cadavers with normal anatomy were studied. Main Outcome Measures Endoscopic visualization was simulated with projected lines from an endoscope to the cervical spine in multiple positions. Results Neck position alone did not affect the extent of endonasal exposure of the upper cervical spine, although there was a trend correlating the extended neck position with more caudal exposure. The greatest impact was with concurrent use of a 30-degree endoscope and neck extension, and more caudal access was achieved by tilting the endoscope against the piriform aperture, using the posterior tip of the hard palate as the fulcrum. Conclusions Concurrent use of a 30-degree endoscope and neck extension increased the degree of exposure down the cervical spine. Maximum endonasal exposure of the upper cervical spine was obtained by maneuvering instruments at the fulcrum of the posterior hard palate and the nares, rather than changing the position of the neck alone. These results complement radiographic morphometric data in Part 1 of this study for preoperative assessment and surgical planning

Endonasal Access to The Upper Cervical Spine: Part 2—Cadaveric Analysis

Objectives The study aims to determine factors that augment endonasal exposure of the cervical spine. Setting We used fluoroscopy and endoscopy to study endonasal visualization of the upper cervical spine. Participants Ten cadavers with normal anatomy were studied. Main Outcome Measures Endoscopic visualization was simulated with projected lines from an endoscope to the cervical spine in multiple positions. Results Neck position alone did not affect the extent of endonasal exposure of the upper cervical spine, although there was a trend correlating the extended neck position with more caudal exposure. The greatest impact was with concurrent use of a 30-degree endoscope and neck extension, and more caudal access was achieved by tilting the endoscope against the piriform aperture, using the posterior tip of the hard palate as the fulcrum. Conclusions Concurrent use of a 30-degree endoscope and neck extension increased the degree of exposure down the cervical spine. Maximum endonasal exposure of the upper cervical spine was obtained by maneuvering instruments at the fulcrum of the posterior hard palate and the nares, rather than changing the position of the neck alone. These results complement radiographic morphometric data in Part 1 of this study for preoperative assessment and surgical planning

Endonasal Access to The Upper Cervical Spine: Part 2—Cadaveric Analysis

Objectives The study aims to determine factors that augment endonasal exposure of the cervical spine. Setting We used fluoroscopy and endoscopy to study endonasal visualization of the upper cervical spine. Participants Ten cadavers with normal anatomy were studied. Main Outcome Measures Endoscopic visualization was simulated with projected lines from an endoscope to the cervical spine in multiple positions. Results Neck position alone did not affect the extent of endonasal exposure of the upper cervical spine, although there was a trend correlating the extended neck position with more caudal exposure. The greatest impact was with concurrent use of a 30-degree endoscope and neck extension, and more caudal access was achieved by tilting the endoscope against the piriform aperture, using the posterior tip of the hard palate as the fulcrum. Conclusions Concurrent use of a 30-degree endoscope and neck extension increased the degree of exposure down the cervical spine. Maximum endonasal exposure of the upper cervical spine was obtained by maneuvering instruments at the fulcrum of the posterior hard palate and the nares, rather than changing the position of the neck alone. These results complement radiographic morphometric data in Part 1 of this study for preoperative assessment and surgical planning