Mechanism of tumor remission by cytomegalovirus in a murine lymphoma model: evidence for involvement of virally induced cellular interleukin-15.

A murine model of B and T cell lymphomas in recipients after hematoablative conditioning for hematopoietic cell transplantation (HCT) has previously revealed a tumor-repressive, metastasis-inhibiting function of murine cytomegalovirus (mCMV). More recently, this prediction from the experimental model was put on trial in several clinical studies that indeed gave evidence for a lower incidence of tumor relapse associated with early reactivation of latent human cytomegalovirus (hCMV) after allogeneic HCT in patients treated against different types of hematopoietic malignancies, including lymphoma and acute as well as chronic leukemias. Due to the limitations inherent to clinical studies, the tumor-repressive role of hCMV remained observational with no approach to clarify mechanisms. Although the tumor-repressive mechanisms of mCMV and hCMV may differ and depend on the type of tumor, experimental approaches in the murine model might give valuable hints for concepts to follow in clinical research. We have previously shown for the liver-adapted A20-derived B cell lymphoma E12E that mCMV does not infect the lymphoma cells for causing cell death by viral cytopathogenicity but triggers tumor-selective apoptosis at a tissue site of tumor metastasis distant from a local site of infection. This finding suggested involvement of a cytokine that triggers apoptosis, directly or indirectly. Here we used a series of differential high-density microarray analyses to identify cellular genes whose expression is specifically upregulated at the site of virus entry only by viruses capable of triggering lymphoma cell apoptosis. This strategy identified interleukin-15 (IL-15) as most promising candidate, eventually confirmed by lymphoma repression with recombinant IL-15.