Editors' ChoiceCancer

Viruses teach T cells to tackle tumors

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Science Translational Medicine  11 Sep 2019:
Vol. 11, Issue 509, eaaz0309
DOI: 10.1126/scitranslmed.aaz0309

Abstract

Oncolytic vaccinia virus expressing leptin enhances T cell clearance of melanomas.

Although cytotoxic T cells use many different effector pathways to kill infected or cancerous cells, they are often ineffective at clearing solid tumors. In some cases, T cells simply do not gain access to the dense tumor tissue. In other instances, T cells become exhausted and incapable of exerting effector function. Tumors drastically modify their local environment by reducing tissue oxygenation and nutrients, rendering T cells metabolically insufficient and hindering their function. Thus, metabolic T cell reprogramming to increase glucose uptake or preserve mitochondrial function can enhance antitumor responses.

In a dramatically different antitumor approach, the burgeoning field of oncolytic virotherapy uses live viruses to infect and destroy tumors while sparing noncancerous cells. Oncolytic viruses can hasten tumor clearance via multiple mechanisms including: direct lysis of infected tumor cells; stimulation of enhanced local and systemic immune responses; modulation of the tumor microenvironment; and provision of virally encoded, secreted immunomodulatory proteins. Several oncolytic viruses have shown promise in preclinical trials and one herpes simplex virus–based treatment is approved by the U.S. Food and Drug Administration for treating advanced melanoma. However, most oncolytic virotherapies do not generate durable responses when used alone.

To sustain antitumor T cells in the harsh tumor microenvironment, Rivadeneira et al. ingeniously co-opted the cytokine leptin to reprogram T cell metabolism. Leptin is known to play a major role in human metabolism and obesity, but this protein has been largely overlooked by tumor immunologists. Taking advantage of T cell expression of leptin receptor at steady state and its up-regulation in tumor-infiltrating T cells, the authors first demonstrated that in vitro incubation with exogenous leptin enhanced T cell metabolism and proliferation. Localized delivery of leptin using oncolytic vaccinia virus (VACV) injected directly into murine tumors improved T cell recruitment into tumors and enhanced T cell mitochondrial content. Compared with the injection of a control VACV, leptin-expressing VACV enhanced survival of tumor-bearing mice by approximately 10 days. Although not compared directly with control VACV, leptin-expressing VACV promoted memory CD8+ T cells that protected against secondary tumor challenge. Much remains to be explored, but promising results from the confined delivery of metabolism-modifying agents to the tumor microenvironment via oncolytic viruses open new avenues for cancer immunotherapies.

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