Editors' ChoiceCancer Immunology

Stress, age, and cancer

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Science Signaling  01 Oct 2019:
Vol. 12, Issue 601, eaaz4717
DOI: 10.1126/scisignal.aaz4717

Stress and advanced age suppress interferon-mediated antitumor immune surveillance and therapy.

Stress has considerable and detrimental effects on health and wellness. It has also been associated with the development of cancers and with worse outcomes in cancer patients undergoing therapy. Yang et al. found that production of the stress hormone glucocorticoid suppressed the efficacy of immunotherapy against tumors in mice. For example, increased serum concentrations of the glucocorticoid corticosterone were seen in mice that underwent a program of social defeat stress, which induces behaviors similar to those seen in humans after bullying or chronic social subordination. Corticosterone increased the expression of the glucocorticoid receptor–encoding gene Tsc22d3 in dendritic cells (DCs), which then failed to produce type I interferon (IFN) upon infiltration into chemical-induced or implanted tumors, thereby failing to induce IFN-dependent antitumor responses in cytotoxic T cells and reducing the efficacy of chemo- and immunotherapy. These effects were mimicked by administration of glucocorticosteroid and prevented by either administration of a glucocorticoid receptor antagonist or DC-specific deletion of Tsc22d3. These findings provide an intercellular molecular mechanism underlying the epidemiological phenomenon of stress on clinical outcomes in cancer patients and show that therapeutic intervention could be beneficial.

IFN signaling is well associated with antitumor effects, both for its antiproliferative action on tumor cells themselves and for its induction of immune cell activity, specifically through promoting antigen presentation, the other side of the coin that is necessary for the success of checkpoint blockade therapies. Relative to other subtypes, triple-negative breast cancer (TNBC) cells typically have greater surface abundance of the immune cell checkpoint receptor programmed cell death ligand 1 (PD-L1), making TNBC an attractive tumor for checkpoint-blocking immunotherapies. However, most trials have been run with patients younger than 60 years of age, although cancer incidence is greater in those older than 60. Sceneay et al. found that IFN signaling and associated antigen presentation in the tumor microenvironment decreased with age both in xenografted mice and in patients with TNBC. Diminished IFN signaling was associated with decreased activation of infiltrating lymphocytes and reduced growth inhibition by the checkpoint-blocking therapies anti–PD-L1 and anti-CTLA4. Adding an agonist of the IFN pathway activator STING improved the efficacy of checkpoint blockade in mice. Such age-associated efficacy is also reportedly seen in mouse models of melanoma. We know that the immune system changes as we age, but this study identifies one of those changes—reduced IFN signaling—that limits the efficacy of immunotherapy. Combined with the above findings about the effects of stress on IFN-mediated immunity, these reports indicate that patient-specific factors such as age and stress, in addition to tumor-intrinsic and microenvironmental factors, should be incorporated into more holistic clinical strategies for patients.

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