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 Blood, 1 February 2008, Vol. 111, No. 3, pp. 1413-1419.
Prepublished online as a Blood First Edition Paper on October 30, 2007; DOI 10.1182/blood-2007-05-089458.

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IMMUNOBIOLOGY

An immune escape screen reveals Cdc42 as regulator of cancer susceptibility to lymphocyte-mediated tumor suppression

Celio A. Marques1, Patricia S. Hähnel1,2, Catherine Wölfel1, Sonja Thaler1, Christoph Huber1, Matthias Theobald1,3, and Martin Schuler1,2

1 Department of Medicine III, Johannes Gutenberg University, Mainz, Germany; 2 Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Essen, Germany; and 3 Department of Hematology and Van Creveld Clinic, University Medical Center Utrecht, Utrecht, the Netherlands

Adoptive cellular immunotherapy inducing a graft-versus-tumor (GVT) effect is the therapeutic mainstay of allogeneic hematopoietic stem cell transplantation (ASCT) for high-risk leukemias. Autologous immunotherapies using vaccines or adoptive transfer of ex vivo–manipulated lymphocytes are clinically explored in patients with various cancer entities. Main reason for failure of ASCT and cancer immunotherapy is progression of the underlying malignancy, which is more prevalent in patients with advanced disease. Elucidating the molecular mechanisms contributing to immune escape will help to develop strategies for the improvement of immunologic cancer treatment. To this end, we have undertaken functional screening and expression cloning of factors mediating resistance to antigen-specific cytotoxic T lymphocytes (CTLs). We have identified Cdc42, a GTPase regulating actin dynamics and growth factor signaling that is highly expressed in invasive cancers, as determinator of cancer cell susceptibility to antigen-specific CTLs in vitro and adoptively transferred immune effectors in vivo. Cdc42 prevents CTL-induced apoptosis via mitogen-activated protein kinase (MAPK) signaling and posttranscriptional stabilization of Bcl-2. Pharmacologic inhibition of MAPK/extracellular signal–regulated kinase (ERK) kinase (MEK) overcomes Cdc42-mediated immunoresistance and activation of Bcl-2 in vivo. In conclusion, Cdc42 signaling contributes to immune escape of cancer. Targeting Cdc42 may improve the efficacy of cancer immunotherapies.


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