Editors' ChoiceCancer Immunology

Immunosuppression even in death

Sci. Signal.  27 Sep 2016:
Vol. 9, Issue 447, pp. ec220
DOI: 10.1126/scisignal.aak9775

Tumors are adept at thwarting an attack from the immune system by releasing immunosuppressive molecules into the tumor microenvironment. Patients with tumors that have areas of cell death called necrosis typically have poor prognosis. Eil et al. found that necrotic sections from melanoma tumors release potassium ions (K+) that shut off activating signals within T cells. The concentration of K+ was greater in the interstitial fluid of mouse or human melanoma tumors than in that of healthy tissues, and the concentration was greatest in areas of dying cells. Inducing cell death with high temperature or freeze-thaw cycles stimulated K+ release from cultured melanoma cells. Adding K+ to cultured CD8+ T cells suppressed the activation of the T cell receptor (TCR); the phosphorylation of a serine-threonine protein kinase (AKT), and mechanistic target of rapamycin (mTOR), which are activated by TCR signaling; and the production of the cytokine interferon-γ (IFN-γ), which is encoded by a gene target of the TCR-AKT–mTOR pathway. Exogenous K+ also restricted the polarization of CD4+ T cells to generate effector T cells but promoted the generation of regulatory T cells. Pharmacologic screening and various follow-up cell culture assays revealed that increased intracellular K+ suppressed AKT-mTOR–mediated T cell activation by stimulating the phosphatase PP2A. Overexpressing the voltage-gated potassium pump Kv1.3 (encoded by KCNA3) in T cells injected into mice promoted K+ efflux and prevented tumor-induced suppression of AKT–mTOR activation and IFN-γ production. Tumor growth was reduced, and survival was extended in mice injected with KCNA3-overexpressing T cells. Although the mechanism between K+ influx and PP2A activation is currently unknown, the findings suggest that immunotherapies engineered to block excessive K+ accumulation in T cells may improve survival in melanoma patients and potentially others (see commentary by Chandy and Norton).

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, N. P. Restifo, Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016). [PubMed]

K. G. Chandy, R. S. Norton, Immunology: Channelling potassium to fight cancer. Nature 537, 497–499 (2016). [PubMed]