genome-wide-rnai-screening-to-identify-host-factors-that-modulate

Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy

High-throughput genome-wide RNAi (RNA interference) screening technology has been widely used for discovering host factors that impact&#160;virus ...

Children's Hospital of Eastern Ontario (CHEO) Research Institute

University of Calgary

Smac mimetic compounds (SMC), a class of drugs that sensitize cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, have proven safe in phase 1 clinical trials in cancer patients. However, because SMCs act by enabling transduction of pro-apoptotic signals, SMC monotherapy may be efficacious only in the subset of patients whose tumors produce large quantities of death-inducing proteins such as inflammatory cytokines. Therefore, we reasoned that SMCs would synergize with agents that stimulate a potent yet safe "cytokine storm." Here we show that oncolytic viruses and adjuvants such as poly(I:C) and CpG induce bystander death of cancer cells treated with SMCs that is mediated by interferon beta (IFN-β), tumor necrosis factor alpha (TNF-α) and/or TNF-related apoptosis-inducing ligand (TRAIL). This combinatorial treatment resulted in tumor regression and extended survival in two mouse models of cancer. As these and other adjuvants have been proven safe in clinical trials, it may be worthwhile to explore their clinical efficacy in combination with SMCs.

Smac mimetics and innate immune stimuli synergize to promote tumor death.

The development of intravital microscopy has provided unprecedented capacity to study the tumor microenvironment in live mice. The dynamic behavior of cancer, stromal, vascular, and immune cells can be monitored in real time, in situ, in both primary tumors and metastatic lesions, allowing treatment responses to be observed at single cell resolution and therapies tracked in vivo. These features provide a unique opportunity to elucidate the cellular mechanisms underlying the biology and treatment of cancer. We describe here a method for imaging the microenvironment of subcutaneous tumors grown in mice using intravital microscopy.

Intravital Microscopy for Imaging the Tumor Microenvironment in Live Mice.

Second mitochondrial activator of caspase (Smac)-mimetic compounds and oncolytic viruses were developed to kill cancer cells directly. However, Smac-mimetic compound and oncolytic virus therapies also modulate host immune responses in ways we hypothesized would complement one another in promoting anticancer T-cell immunity. We show that Smac-mimetic compound and oncolytic virus therapies synergize in driving CD8T-cell responses toward tumors through distinct activities. Smac-mimetic compound treatment with LCL161 reinvigorates exhausted CD8T cells within immunosuppressed tumors by targeting tumor-associated macrophages for M1-like polarization. Oncolytic virus treatment with vesicular stomatitis virus (VSV) promotes CD8T-cell accumulation within tumors and CD8T-cell activation within the tumor-draining lymph node. When combined, LCL161 and VSVtherapy engenders CD8T-cell-mediated tumor control in several aggressive mouse models of cancer. Smac-mimetic compound and oncolytic virus therapies are both in clinical development and their combination therapy represents a promising approach for promoting anticancer T-cell immunity.Oncolytic viruses (OV) and second mitochondrial activator of caspase (Smac)-mimetic compounds (SMC) synergistically kill cancer cells directly. Here, the authors show that SMC and OV therapies combination also synergize in vivo by promoting anticancer immunity through an increase in CD8T-cell response.

Smac mimetics and oncolytic viruses synergize in driving anticancer T-cell responses through complementary mechanisms.

Neutrophils are the most abundant type of white blood cell, and are an essential component of the innate immune system. They characteristically arrive rapidly at sites of infection and injury, and release a variety of cytokines and toxic molecules to eliminate pathogens and elicit an acute inflammatory response. Research into the function of neutrophils in cancer suggest they have divergent roles. Indeed, while most studies have found neutrophils to be associated with cancer progression, others have also documented anticancer effects. In this review, we describe the investigations into neutrophil populations that have been implicated in promoting tumor growth and metastasis as well those demonstrating antitumor functions. The collective research suggests a complex role for neutrophils in cancer biology, which raises the prospect of their targeting for the treatment of cancer.

Article	Year
Smac mimetics and innate immune stimuli synergize to promote tumor death. Nature biotechnology\| PubMed ID: 24463573	2014
Intravital Microscopy for Imaging the Tumor Microenvironment in Live Mice. Methods in molecular biology (Clifton, N.J.)\| PubMed ID: 27581025	2016
Smac mimetics and oncolytic viruses synergize in driving anticancer T-cell responses through complementary mechanisms. Nature communications\| PubMed ID: 28839138	2017
The complex interplay between neutrophils and cancer. Cell and tissue research\| PubMed ID: 29427051	2018

Douglas J. Mahoney

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