The role of ORAI and STIM proteins in T cell dependent anti-tumor immunosurveillance

• Applicant: Dr. Carl Weidinger
• Subject Area: Hematology, Oncology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 222118602

Store-operated calcium entry (SOCE) through ORAI and STIM proteins controls the function of many immune cells. Loss of function mutations in ORAI1 or STIM1 in human patients and targeted deletion of these genes in mice severely impair the function of CD8+ cytotoxic T lymphocytes (CTL) and regulatory T (Treg) cells causing immunodeficiency and autoimmunity. CTL are pivotal for the elimination of cancer cells, whereas Treg cells promote cancer proliferation by suppressing antitumor immune responses. ORAI1- and STIM1-deficient patients were shown to develop EBV-associated lymphoma as well as Kaposi sarcoma, suggesting that SOCE might be critical for tumor immunosurveillance. Based on these findings, I hypothesize that SOCE is a key regulator of tumor immunosurveillance and propose the following aims: I will test whether SOCE in CTL is required for antitumor immunity and investigate the mechanism by which SOCE controls CTL functions against tumors by using mice with T cell-specific deletion of Stim and Orai genes. I will investigate whether SOCE is required for the ability of Treg cells to suppress antitumor immunity by studying Treg cells in tumors induced in mice with Treg-specific deletion of Stim and Orai genes. To date it is unknown, which role SOCE is playing in tumor surveillance: Depending on which T cell subtype, CTL or Treg cells, predominantly infiltrates a tumor, SOCE might contribute to either tumor rejection or immune evasion, respectively. In addition, different SOCE thresholds for CTL and Treg function might be existing. I will therefore use conditionally gene-targeted mice lacking expression of Orai1, Stim1, Stim2 or both Stim1/Stim2 genes in T cells to analyze the role of SOCE for CTL and Treg function in tumor immunosurveillance. Since SOCE is impaired to different degrees in T cells from these mice, I will be able to quantify the role of SOCE for the function of CTL and Treg cells in immune responses to tumors.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Stefan Feske