Role of CD154 in cancer pathogenesis and immunotherapy

• CD154 is a co-stimulatory molecule known for its role in inflammatory and autoimmune diseases.
• CD154 and its receptor, CD40 are expressed in many types of tumors.
• The CD154/CD40 interaction is capable of inducing the proliferation and rescue from apoptosis of tumor cells.
• CD154 activates anti-tumoral immunity, and by engaging CD40 may induce apoptosis of tumor cells.
• The role of CD154 in cancer immunotherapy was demonstrated in animal models and clinically assessed in patients.

Many factors and molecules have been investigated as potential players in the pathogenesis or immunosurveillance of cancer. Among these, CD154 has been recognized as a co-stimulatory molecule with high potential for treating cancer, in addition to its contribution in the development of the disease. CD154 was initially described for its pivotal role in T cell-dependent humoral responses via an interaction with its classical receptor, CD40. Subsequent studies showed that CD154 is also implicated in cell-mediated immunity and inflammation via an interaction with CD40 alone or in combination with newly identified receptors, members of the integrin family, leading to the development of chronic inflammatory and autoimmune diseases. In the current article, we present an overview of the role of CD154 as a potential etiological factor in tumors inducing proliferation of malignant cells, their rescue from apoptosis and their invasiveness. In addition, this review describes the immuno-regulatory functions of CD154 against cancer reflected by its stimulation of antigen-presenting cells and the subsequent activation of effector cells, its enhancement of malignant cells’ immunogenicity, its modulation of immune settings around tumors, and its initiation of proliferation inhibiting effects in malignant cells. In vitro as well as in vivo studies are outlined and a particular attention is given to clinical studies and progress reached at this point. Findings reviewed herein will improve our knowledge of the role of the CD154 system in cancers from causative to immunotherapeutic functions, paving the way for the identification of new targets for prevention and/or treatment of malignant disorders.