Search

Background: Dying tumor cells release intracellular potassium (K(+)), raising extracellular K(+) ([K(+)](e)) in the tumor microenvironment (TME) to 40–50 mM (high-[K(+)](e)). Here, we investigated the effect of high-[K(+)](e) on T cell functions. Materials and Methods: Functional impacts of high-[K(+)](e) on human T cells were determined by cellular, molecular, and imaging assays. Results: Exposure to high-[K(+)](e) suppressed the proliferation of central memory and effector memory T cells, while T memory stem cells were unaffected. High-[K(+)](e) inhibited T cell cytokine production and dampened antitumor cytotoxicity, by modulating the Akt signaling pathway. High-[K(+)](e) caused significant upregulation of the immune checkpoint protein PD-1 in activated T cells. Although the number of K(Ca)3.1 calcium-activated potassium channels expressed in T cells remained unaffected under high-[K(+)](e), a novel K(Ca)3.1 activator, SKA-346, rescued T cells from high-[K(+)](e)-mediated suppression. Conclusion: High-[K(+)](e) represents a so far overlooked secondary checkpoint in cancer. K(Ca)3.1 activators could overcome such “ionic-checkpoint”-mediated immunosuppression in the TME, and be administered together with known PD-1 inhibitors and other cancer therapeutics to improve outcomes.

Background:Dying tumor cells release intracellular potassium (K+), raising extracellular K+([K+]e) in the tumor microenvironment (TME) to 40–50 mM (high-[K+]e). Here, we investigated the effect of high-[K+]eon T cell functions. Materials and Methods:Functional impacts of high-[K+]eon human T cells were determined by cellular, molecular, and imaging assays. Results:Exposure to high-[K+]esuppressed the proliferation of central memory and effector memory T cells, while T memory stem cells were unaffected. High-[K+]einhibited T cell cytokine production and dampened antitumor cytotoxicity, by modulating the Akt signaling pathway. High-[K+]ecaused significant upregulation of the immune checkpoint protein PD-1 in activated T cells. Although the number of KCa3.1 calcium-activated potassium channels expressed in T cells remained unaffected under high-[K+]e, a novel KCa3.1 activator, SKA-346, rescued T cells from high-[K+]e-mediated suppression. Conclusion:High-[K+]erepresents a so far overlooked secondary checkpoint in cancer. KCa3.1 activators could overcome such “ionic-checkpoint”-mediated immunosuppression in the TME, and be administered together with known PD-1 inhibitors and other cancer therapeutics to improve outcomes.

[Image: see text] We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated K(V)1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to K(V)1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for K(V)1.3 over other channels, receptors, transporters, and enzymes. EgK5 suppresses antigen-triggered proliferation of effector memory T cells, a subset enriched among pathogenic autoreactive T cells in autoimmune disease. PET-CT imaging with (18)F-labeled EgK5 shows accumulation of the peptide in large and small joints of rodents. In keeping with its arthrotropism, EgK5 treats disease in a rat model of rheumatoid arthritis. It was also effective in treating disease in a rat model of atopic dermatitis. No signs of toxicity are observed at 10–100 times the in vivo dose. EgK5 shows promise for clinical development as a therapeutic for autoimmune diseases.

Author(s): Ong, Seow Theng; Liu, Sanling; Bajaj, Saumya; Zhao, Yue; Tanner, Mark R; Chang, Shih Chieh; Zhang, Yong; Krishnarjuna, Bankala; Ng, Xuan Rui; Morales, Rodrigo AV; Ming, Wei Chen; Luo, Dahai; Patel, Dharmeshkumar; Yasmin, Sabina; Ng, Jeremy Jun Heng; Nguyen, Hai M; Abbas, El Sahili; Lescar, Julien; Patil, Rahul; Charman, Susan A; Robins, Edward; Goggi, Julian; Peng, Wen Tan; Sadasivam, Pragalath; Ramasamy, Boominathan; SV, Hartimath; Dhawan, Vikas; Bednenko, Janna; Colussi, Paul; Wulff, Heike; Zhang, Longhua; Pennington, Michael; Kuyucak, Serdar; Norton, Raymond S; Beeton, Christine; Tian, Changlin; Chandy, George

Connective tissue diseases of the skin are characterized by excessive collagen deposition in the skin and internal organs. Fibroblasts play a pivotal role in the clinical presentation of these conditions. Nuclear receptor peroxisome-proliferator activated receptors (PPARs) are therapeutic targets for dermal fibrosis, but the contribution of the different PPAR subtypes are poorly understood. Particularly, the role of fibroblast PPARβ/δ in dermal fibrosis has not been elucidated. Thus, we generated a mouse strain with selective deletion of PPARβ/δ in the fibroblast (FSPCre-Pparb/d−/−) and interrogated its epidermal and dermal transcriptome profiles. We uncovered a downregulated gene, leucine-rich alpha-2-glycoprotein-1 (Lrg1), of previously unknown function in skin development and architecture. Our findings suggest that the regulation of Lrg1 by PPARβ/δ in fibroblasts is an important signaling conduit integrating PPARβ/δ and TGFβ1-signaling networks in skin health and disease. Thus, the FSPCre-Pparb/d−/− mouse model could serve as a novel tool in the current gunnery of animal models to better understand dermal fibrosis.