Immune System, Friend or Foe of Oncolytic Virotherapy?

Abstract

Oncolytic viruses (OVs) are an emerging class of targeted anticancer therapies designed to selectively infect, replicate in, and lyse malignant cells without causing harm to normal, healthy tissues. In addition to direct oncolytic activity, OVs have shown dual promise as immunotherapeutic agents. The presence of viral infection and subsequently generated immunogenic tumor cell death trigger innate and adaptive immune responses that mediate further tumor destruction. However, antiviral immune responses can intrinsically limit OV infection, spread, and overall therapeutic efficacy. Host immune system can act both as a barrier as well as a facilitator and sometimes both at the same time based on the phase of viral infection. Thus, manipulating the host immune system to minimize antiviral responses and viral clearance while still promoting immune-mediated tumor destruction remains a key challenge facing oncolytic virotherapy. Recent clinical trials have established the safety, tolerability, and efficacy of virotherapies in the treatment of a variety of malignancies. Most notably, talimogene laherparepvec (T-VEC), a genetically engineered oncolytic herpesvirus-expressing granulocyte macrophage colony stimulating factor, was recently approved for the treatment of melanoma, representing the first OV to be approved by the FDA as an anticancer therapy in the US. This review discusses OVs and their antitumor properties, their complex interactions with the immune system, synergy between virotherapy and existing cancer treatments, and emerging strategies to augment the efficacy of OVs as anticancer therapies.

Keywords: adaptive immunity; cancer; immunotherapy; innate immunity; oncolytic virus.

Figure 1

Oncolytic viruses (OVs) mediate tumor cell destruction by two main mechanisms: (1) direct lysis of infected cells, OVs selectively infect malignant cells, hijacking their cellular transcription, and translation mechanisms in order to replicate. Termination of the viral replication cycle induces tumor cell lysis and release of infectious viral progeny. Oncolysis also releases viral particles, tumor-associated antigens, and cellular damage-associated molecular patterns like calreticulin, heat shock proteins, and cellular ATP in a highly inflammatory process, termed “immunogenic cell death” and (2) induction of host antitumor immune responses. Cellular detection of viral infection and the products of oncolysis trigger the rapid activation of host antiviral responses and influx of immune cells that mediate the destruction of residual infected and uninfected tumor cells. The direct recognition and killing of tumor cells is primarily mediated by natural killer cells of the innate immune system and tumor antigen-specific CD8+ cytotoxic T lymphocytes of the adaptive immune system.

Figure 2

Immunologic barriers to successful oncolytic virotherapy: (1) oncolytic virus delivery to tumor sites is impeded by the presence of neutralizing antibodies, complement proteins, and sequestration in organs such as the liver and spleen; (2) cellular antiviral responses, such as type I interferon signaling limits viral replication within tumor cells; (3) destruction of infected tumor cells by cells of the innate immune system (neutrophils, macrophages, NK cells) prematurely terminates viral infection; (4) tumor-induced immunosuppression (elaboration of immunosuppressive cytokines, accumulation of regulatory T cells, overexpression of negative checkpoint regulators of T cell function) inhibits the generation and effector functions of antigen-specific antitumor immune responses.