Cell Death in the Tumor Microenvironment: Implications for Cancer Immunotherapy.

The physiological fate of cells that die by apoptosis is their prompt and efficient removal by efferocytosis. During these processes, apoptotic cells release intracellular constituents that include purine nucleotides, lysophosphatidylcholine (LPC), and Sphingosine-1-phosphate (S1P) that induce migration and chemo-attraction of phagocytes as well as mitogens and extracellular membrane-bound vesicles that contribute to apoptosis-induced compensatory proliferation and alteration of the extracellular matrix and the vascular network. Additionally, during efferocytosis, phagocytic cells produce a number of anti-inflammatory and resolving factors, and, together with apoptotic cells, efferocytic events have a homeostatic function that regulates tissue repair. These homeostatic functions are dysregulated in cancers, where, aforementioned events, if not properly controlled, can lead to cancer progression and immune escape. Here, we summarize evidence that apoptosis and efferocytosis are exploited in cancer, as well as discuss current translation and clinical efforts to harness signals from dying cells into therapeutic strategies.

Use of Electronic Health Records to Develop and Implement a Silent Best Practice Alert Notification System for Patient Recruitment in Clinical Research: Quality Improvement Initiative.

BACKGROUND: Participant recruitment, especially for frail, elderly, hospitalized patients, remains one of the greatest challenges for many research groups. Traditional recruitment methods such as chart reviews are often inefficient, low-yielding, time consuming, and expensive. Best Practice Alert (BPA) systems have previously been used to improve clinical care and inform provider decision making, but the system has not been widely used in the setting of clinical research. OBJECTIVE: The primary objective of this quality-improvement initiative was to develop, implement, and refine a silent Best Practice Alert (sBPA) system that could maximize recruitment efficiency. METHODS: The captured duration of the screening sessions for both methods combined with the allotted research coordinator hours in the Emerald-COPD (chronic obstructive pulmonary disease) study budget enabled research coordinators to estimate the cost-efficiency. RESULTS: Prior to implementation, the sBPA system underwent three primary stages of development. Ultimately, the final iteration produced a system that provided similar results as the manual Epic Reporting Workbench method of screening. A total of 559 potential participants who met the basic prescreen criteria were identified through the two screening methods. Of those, 418 potential participants were identified by both methods simultaneously, 99 were identified only by the Epic Reporting Workbench Method, and 42 were identified only by the sBPA method. Of those identified by the Epic Reporting Workbench, only 12 (of 99, 12.12%) were considered eligible. Of those identified by the sBPA method, 30 (of 42, 71.43%) were considered eligible. Using a side-by-side comparison of the sBPA and the traditional Epic Reporting Workbench method of screening, the sBPA screening method was shown to be approximately four times faster than our previous screening method and estimated a projected 442.5 hours saved over the duration of the study. Additionally, since implementation, the sBPA system identified the equivalent of three additional potential participants per week. CONCLUSIONS: Automation of the recruitment process allowed us to identify potential participants in real time and find more potential participants who meet basic eligibility criteria. sBPA screening is a considerably faster method that allows for more efficient use of resources. This innovative and instrumental functionality can be modified to the needs of other research studies aiming to use the electronic medical records system for participant recruitment.

Phosphatidylserine Sensing by TAM Receptors Regulates AKT-Dependent Chemoresistance and PD-L1 Expression.

Tyro3, Axl, and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases that bind vitamin K-dependent endogenous ligands, Protein S (ProS), and growth arrest-specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radioresistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment that can suppress host antitumor immunity. In the present study, we utilized TAM-IFNγR1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor has a unique pattern of activation by Gas6 or ProS, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity. In addition, we leveraged this system to engineer epithelial cells that express wild-type TAM receptors and show that although each receptor can promote PS-mediated efferocytosis, AKT-mediated chemoresistance, as well as upregulate the immune checkpoint molecule PD-L1 on tumor cells, Mertk is most dominant in the aforementioned pathways. Functionally, TAM receptor-mediated efferocytosis could be partially blocked by PS-targeting antibody 11.31 and Annexin V, demonstrating the existence of a PS/PS receptor (i.e., TAM receptor)/PD-L1 axis that operates in epithelial cells to foster immune escape. These data provide a rationale that PS-targeting, anti-TAM receptor, and anti-PD-L1-based therapeutics will have merit as combinatorial checkpoint inhibitors.Implications: Many tumor cells are known to upregulate the immune checkpoint inhibitor PD-L1. This study demonstrates a role for PS and TAM receptors in the regulation of PD-L1 on cancer cells. Mol Cancer Res; 15(6); 753-64. ©2017 AACR.