Molecular Circuits of Immune Sensing and Response to Oncolytic Virotherapy.

Oncolytic virotherapy is a promising immunotherapy approach for cancer treatment that utilizes viruses to preferentially infect and eliminate cancer cells while stimulating the immune response. In this review, we synthesize the current literature on the molecular circuits of immune sensing and response to oncolytic virotherapy, focusing on viral DNA or RNA sensing by infected cells, cytokine and danger-associated-signal sensing by neighboring cells, and the subsequent downstream activation of immune pathways. These sequential sense-and-response mechanisms involve the triggering of molecular sensors by viruses or infected cells to activate transcription factors and related genes for a breadth of immune responses. We describe how the molecular signals induced in the tumor upon virotherapy can trigger diverse immune signaling pathways, activating both antigen-presenting-cell-based innate and T cell-based adaptive immune responses. Insights into these complex mechanisms provide valuable knowledge for enhancing oncolytic virotherapy strategies.

Oncolytic alphavirus replicons mediated recruitment and activation of T cells.

Oncolytic viruses show promise in enhancing tumor immunogenicity by releasing immunogenic signals during tumor cell infection and lysis. In this study, we improved the virus-induced tumor immunogenicity of recombinant Semliki Forest virus (rSFV)-based replicon particles by encoding immunogenic cytokines such as C-X-C motif chemokine ligand 10 (CXCL10), FMS-like tyrosine kinase 3 ligand (Flt3L), or interferon-gamma (IFN-Æ´). Real-time imaging and flow cytometry of human cancer cell-based monolayer and spheroid cultures, using LNCaP or PANC-1 cells, revealed effective infection and transgene expression in both models. LNCaP cells exhibited higher and earlier rSFV infection compared to PANC-1 cells. While infected LNCaP cells effectively triggered immune recruitment and T cell activation even without encoding cytokines, PANC-1 cells demonstrated improved immune responses only when infected with replicons encoding cytokines, particularly IFN-Æ´, which enhanced tumor immunogenicity irrespective of cancer cell susceptibility to infection. Our study demonstrates that despite innate phenotypic disparities in cancer cells, rSFV-based replicons encoding cytokines can potentially generate effective immune responses in the tumor.

A systematic analysis on the clinical safety and efficacy of onco-virotherapy.

Several onco-virotherapy candidates have been developed and clinically evaluated for the treatment of cancer, and several are approved for clinical use. In this systematic review we explored the clinical impact of onco-virotherapy compared to other cancer therapies by analyzing factors such as trial design, patient background, therapy design, delivery strategies, and study outcomes. For this purpose, we retrieved clinical studies from three platforms: ClinicalTrials.gov, PubMed, and EMBASE. We found that most studies were performed in patients with advanced and metastatic tumors, using a broad range of genetically engineered vectors and mainly administered intratumorally. Therapeutic safety was the most frequently assessed outcome, while relatively few studies focused on immunological antitumor responses. Moreover, only 59 out of 896 clinical studies were randomized controlled trials reporting comparative data. This systemic review thus reveals the need of more, and better controlled, clinical studies to increase our understanding on the application of onco-virotherapy either as a single treatment or in combination with other cancer immunotherapies.

Resistance Mechanisms Influencing Oncolytic Virotherapy, a Systematic Analysis.

Resistance to therapy is a frequently observed phenomenon in the treatment of cancer, and as with other cancer therapeutics, therapies based on oncolytic viruses also face the challenges of resistance, such as humoral and cellular antiviral responses, and tumor-associated interferon-mediated resistance. In order to identify additional mechanisms of resistance that may contribute to therapeutic failure, we developed a systematic search strategy for studies published in PubMed. We analyzed 6143 articles on oncolytic virotherapy and found that approximately 8% of these articles use resistance terms in the abstract and/or title. Of these 439 articles, 87 were original research. Most of the findings reported pertain to resistance mediated by tumor-cell-dependent interferon signaling. Yet, mechanisms such as epigenetic modifications, hypoxia-mediated inhibition, APOBEC-mediated resistance, virus entry barriers, and spatiotemporal restriction to viral spread, although not frequently assessed, were demonstrated to play a major role in resistance. Similarly, our results suggest that the stromal compartment consisting of, but not limited to, myeloid cells, fibroblasts, and epithelial cells requires more study in relation to therapy resistance using oncolytic viruses. Thus, our findings emphasize the need to assess the stromal compartment and to identify novel mechanisms that play an important role in conferring resistance to oncolytic virotherapy.

Cellular Adaptation Relies on Regulatory Proteins Having Episodic Memory: Proteins Modulate Cell Metabolism and Reproduction by Remembering, Transmitting, and Using Data on the Environment.

The ability to memorize changes in the environment is present at all biological levels, from social groups and individuals, down to single cells. Trans-generational memory is embedded subcellularly through genetic and epigenetic mechanisms. Evidence that cells process and remember features of the immediate environment using protein sensors is reviewed. It is argued that this mnemonic ability is encapsulated within the protein conformational space and lasts throughout its lifetime, which can overlap with the lifespan of the organism. Means to determine diachronic changes in protein activity are presented.