A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity

Abstract

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are required to protect the human body against cancer. Ca²⁺ is a key metabolic factor for lymphocyte function and cancer homeostasis. We analysed the Ca²⁺ dependence of CTL and NK cell cytotoxicity against cancer cells and found that CTL have a bell-shaped Ca²⁺ dependence with an optimum for cancer cell elimination at rather low [Ca²⁺]_ext (23–630 μm) and [Ca²⁺]_int (122–334 nm). This finding predicts that a partial inhibition of Orai1 should increase (rather than decrease) cytotoxicity of CTL at [Ca²⁺]_ext higher than 630 μm. We tested this hypothesis in CTL and indeed found that partial down-regulation of Orai1 by siRNA increases the efficiency of cancer cell killing. We found two mechanisms that may account for the Ca²⁺ optimum of cancer cell killing: 1) Migration velocity and persistence have a moderate optimum between 500 and 1000 μm [Ca²⁺]_ext in CTL, and 2) lytic granule release at the immune synapse between CTL and cancer cells is increased at 146 μm comparted to 3 or 800 μm, compatible with the Ca²⁺ optimum for cancer cell killing. It has been demonstrated in many cancer cell types that Orai1-dependent Ca²⁺ signals enhance proliferation. We propose that a decrease of [Ca²⁺]_ext or partial inhibition of Orai1 activity by selective blockers in the tumor microenvironment could efficiently reduce cancer growth by simultaneously increasing CTL and NK cell cytotoxicity and decreasing cancer cell proliferation.

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