Level of expression of MHCI-presented neoepitopes influences tumor rejection by neoantigen-specific CD8+ T cells.

Neoantigen-targeted therapy holds an array of benefits for cancer immunotherapy, but the identification of peptide targets with tumor rejection capacity remains a limitation. To better define the criteria dictating tumor rejection potential, we examined the capacity of high-magnitude T cell responses induced towards several distinct neoantigen targets to regress MC38 tumors. Surprisingly, despite their demonstrated immunogenicity, vaccine-induced T-cell responses were unable to regress established MC38 tumors or prevent tumor engraftment in a prophylactic setting.

Pyroptosis activates conventional type I dendritic cells to mediate the priming of highly functional anticancer T cells.

Background: Initiation of antitumor immunity is reliant on the stimulation of dendritic cells (DCs) to present tumor antigens to naïve T cells and generate effector T cells that can kill cancer cells. Induction of immunogenic cell death after certain types of cytotoxic anticancer therapies can stimulate T cell-mediated immunity. However, cytotoxic therapies simultaneously activate multiple types of cellular stress and programmed cell death; hence, it remains unknown what types of cancer cell death confer superior antitumor immunity.

Determinants for Antitumor and Protumor Effects of Programmed Cell Death.

Cytotoxic anticancer therapies activate programmed cell death in the context of underlying stress and inflammatory signaling to elicit the emission of danger signals, cytokines, and chemokines. In a concerted manner, these immunomodulatory secretomes stimulate antigen presentation and T cell-mediated anticancer immune responses. In some instances, cell death-associated secretomes attract immunosuppressive cells to promote tumor progression.

LAMP3/CD63 Expression in Early and Late Endosomes in Human Vaginal Epithelial Cells Is Associated with Enhancement of HSV-2 Infection.

Herpes simplex virus 2 (HSV-2) is a lifelong sexually transmitted virus that disproportionately infects women through heterosexual transmission in the vaginal tract. The vaginal epithelium is known to be highly susceptible to HSV-2 infection; however, the cellular mechanism of HSV-2 uptake and replication in vaginal epithelium has not been extensively studied. Previously, we observed that lysosomal-associated membrane protein-3 (LAMP3/CD63) was among the highly upregulated genes during HSV-2 infection of human vaginal epithelial cell line VK2, leading us to posit that LAMP3/CD63 may play a role in HSV-2 infection.

Viral-mediated activation and inhibition of programmed cell death.

Viruses are ubiquitous intracellular genetic parasites that heavily rely on the infected cell to complete their replication life cycle. This dependency on the host machinery forces viruses to modulate a variety of cellular processes including cell survival and cell death. Viruses are known to activate and block almost all types of programmed cell death (PCD) known so far.

A Combination of Chemotherapy and Oncolytic Virotherapy Sensitizes Colorectal Adenocarcinoma to Immune Checkpoint Inhibitors in a cDC1-Dependent Manner.

Immune checkpoint therapy has shown great promise in the treatment of cancers with a high mutational burden, such as mismatch repair-deficient colorectal carcinoma (dMMR CRC). However, many patients fail to respond to immune checkpoint therapy. Using a mouse model of dMMR CRC, we demonstrated that tumors can be further sensitized to immune checkpoint therapy by using a combination of low-dose chemotherapy and oncolytic HSV-1.

Immune checkpoint blockade in triple negative breast cancer influenced by B cells through myeloid-derived suppressor cells.

Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. Clinical trials for TNBC employing immune checkpoint blockade in combination with chemotherapy show modest prognostic benefit, but the percentage of patients that respond to treatment is low, and patients often succumb to relapsed disease. Here, we show that a combination immunotherapy platform utilizing low dose chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) increases tumor-infiltrating lymphocytes, in otherwise immune-bare tumors, allowing 60% of mice to achieve durable tumor regression when treated with immune checkpoint blockade.

Tumor-intrinsic determinants of immunogenic cell death modalities.

The immune system can recognize tumor cells to mount antigen-specific T cell response. Central to the establishment of T cell-mediated adaptive immunity are the inflammatory events that facilitate antigen presentation by stimulating the expression of MHC and costimulatory molecules and the secretion of pro-inflammatory cytokines. Such inflammatory events can be triggered upon cytotoxic treatments that induce immunogenic cancer cell death modalities.

TRIM26 Facilitates HSV-2 Infection by Downregulating Antiviral Responses through the IRF3 Pathway.

Herpes simplex virus type 2 (HSV-2) is the primary cause of genital herpes which results in significant morbidity and mortality, especially in women, worldwide. HSV-2 is transmitted primarily through infection of epithelial cells at skin and mucosal surfaces. Our earlier work to examine interactions between HSV-2 and vaginal epithelial cells demonstrated that infection of the human vaginal epithelial cell line (VK2) with HSV-2 resulted in increased expression of TRIM26, a negative regulator of the Type I interferon pathway.

Cytokines in oncolytic virotherapy.

Tumors represent a hostile environment for the effector cells of cancer immunosurveillance. Immunosuppressive receptors and soluble or membrane-bound ligands are abundantly exposed and released by malignant entities and their stromal accomplices. As a consequence, executioners of antitumor immunity inefficiently navigate across cancer tissues and fail to eliminate malignant targets.

De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors.

Cancer immunotherapies using monoclonal antibodies to block inhibitory checkpoints are showing durable remissions in many types of cancer patients, although the majority of breast cancer patients acquire little benefit. Human melanoma and lung cancer patient studies suggest that immune checkpoint inhibitors are often potent in patients that already have intratumoral T cell infiltrate; although it remains unknown what types of interventions can result in an intratumoral T cell infiltrate in breast cancer. Using non-T cell-inflamed mammary tumors, we assessed what biological processes and downstream inflammation can overcome the barriers to spontaneous T cell priming.

Enhanced immunotherapeutic profile of oncolytic virus-based cancer vaccination using cyclophosphamide preconditioning.

Despite a sizeable body of research, the efficacy of therapeutic cancer vaccines remains limited when applied as sole agents. By using a prime:boost approach involving two viral cancer vaccines, we were able to generate large tumor-specific CD8 T-cell responses in a murine model of disseminated pulmonary melanoma. Significant increases in the number and quality of circulating effector T-cells were documented when low-dose cyclophosphamide (CTX) was administered pre-vaccination to tumor-bearing but not tumor-free hosts.

Pre-surgical neoadjuvant oncolytic virotherapy confers protection against rechallenge in a murine model of breast cancer.

The use of oncolytic viruses (OVs) for cancer treatment is emerging as a successful strategy that combines the direct, targeted killing of the cancer with the induction of a long-lasting anti-tumor immune response. Using multiple aggressive murine models of triple-negative breast cancer, we have recently demonstrated that the early administration of oncolytic Maraba virus (MRB) prior to surgical resection of the primary tumor is sufficient to minimize the metastatic burden, protect against tumor rechallenge, cure a fraction of the mice and sensitize refractory tumors to immune checkpoint blockade without the need for further treatment. Here, we apply our surgical model to other OVs: Vesicular stomatitis virus (VSV), Adenovirus (Ad), Reovirus (Reo) and Herpes simplex virus (HSV) and show that all of the tested OVs could positively change the outcome of the treated animals.

Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis.

Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells.

HDACi Delivery Reprograms Tumor-Infiltrating Myeloid Cells to Eliminate Antigen-Loss Variants.

Immune recognition of tumor-expressed antigens by cytotoxic CD8 T cells is the foundation of adoptive T cell therapy (ACT) and has been shown to elicit significant tumor regression. However, therapy-induced selective pressure can sculpt the antigenicity of tumors, resulting in outgrowth of variants that lose the target antigen. We demonstrate that tumor relapse from ACT and subsequent oncolytic viral vaccination can be prevented using class I HDACi, MS-275.

Critical Interactions between Immunogenic Cancer Cell Death, Oncolytic Viruses, and the Immune System Define the Rational Design of Combination Immunotherapies.

Oncolytic viruses (OVs) are multimodal cancer therapeutics, with one of their dominant mechanisms being in situ vaccination. There is a growing consensus that optimal cancer therapies should generate robust tumor-specific immune responses. Immunogenic cell death (ICD) is a paradigm of cellular demise culminating in the spatiotemporal release of danger-associated molecular patterns that induce potent anticancer immunity.

The role of oncolytic virus immunotherapies to subvert cancer immune evasion.

ABSTRACT  Despite huge economic and intellectual investments, developing effective cancer treatments continues to be an overarching challenge. Engineered oncolytic viruses (OVs) present self-amplifying immunotherapy platforms capable of preferential cytotoxicity to cancer cells and simultaneous activation of host anti-tumor immunity. In preclinical studies, OVs are showing potent therapeutic effects when used in combination with other immune therapy strategies.

Combining oncolytic HSV-1 with immunogenic cell death-inducing drug mitoxantrone breaks cancer immune tolerance and improves therapeutic efficacy.

Although antitumor activity of herpes simplex virus 1 (HSV-1) ICP0 null oncolytic vectors has been validated in murine breast cancer models, oncolytic virus treatment alone is insufficient to break immune tolerance. Thus, we investigated enhancing efficacy through combination therapy with the immunogenic cell death-inducing chemotherapeutic drug, mitoxantrone. Despite a lack of enhanced cytotoxicity in vitro, HSV-1 ICP0 null oncolytic virus KM100 with 5 μmol/L mitoxantrone provided significant survival benefit to BALB/c mice bearing Her2/neu TUBO-derived tumors.

Rewiring cancer cell death to enhance oncolytic viro-immunotherapy.

Oncolytic viruses are novel immunotherapeutic agents that appear to mediate potent antineoplastic effects in both preclinical and clinical settings. Recent studies demonstrate that manipulating the mechanisms whereby cancer cells die in the course of oncolytic virotherapy has potential to boost anticancer immune responses.

Immunogenic HSV-mediated oncolysis shapes the antitumor immune response and contributes to therapeutic efficacy.

Within the oncolytic virus field, the extent of virus replication that is essential for immune stimulation to control tumor growth remains unresolved. Using infected cell protein 0 (ICP0)-defective oncolytic Herpes simplex virus type 1 (HSV-1) and HSV-2 viruses (dICP0 and dNLS) that show differences in their in vitro replication and cytotoxicity, we investigated the inherent features of oncolytic HSV viruses that are required for potent antitumor activity. In vitro, the HSV-2 vectors showed rapid cytotoxicity despite lower viral burst sizes compared to HSV-1 vectors.

Oncolytic virotherapy and immunogenic cancer cell death: sharpening the sword for improved cancer treatment strategies.

Oncolytic viruses are novel immunotherapeutics with increasingly promising outcomes in cancer patient clinical trials. Preclinical and clinical studies have uncovered the importance of virus-induced activation of antitumor immune responses for optimal therapeutic efficacy. Recently, several classes of chemotherapeutics have been shown to cause immunogenic cancer cell death characterized by the release of immunomodulatory molecules that activate antigen-presenting cells and thus trigger the induction of more potent anticancer adaptive immune responses.

The fight between the teleost fish immune response and aquatic viruses.

Teleost fish represent a transition point on the phylogenetic spectrum between invertebrates that depend only on innate immunity and mammals that heavily depend on adaptive immunity. The major mechanisms of the teleost fish innate immune response are suggested to be similar to mammals, although fine details of the process require further studies. Within the innate immune response the type I interferon (IFN) system is an essential innate antiviral component that protects fish from some virus infections.