Donor CD4 T Cells Are Critical in Allogeneic Stem Cell Transplantation against Murine Solid Tumor

¹Division of Host Defense, Research Center for Prevention of Infectious Disease, Medical Institute of Bioregulation and ²Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan and ³Department of General Surgical Science, Graduate School of Medicine, Course of Medical Sciences, Gunma University, Gunma, Japan

^* To whom correspondence should be addressed. E-mail: etom{at}uro.med.kyushu-u.ac.jp.

	Abstract

Nonmyeloablative allogeneic stem cell transplantation (SCT) has been used for various malignancies, although detailed mechanisms of antitumor effects remain unclear. We showed that a nonmyeloablative allogeneic SCT regimen, which consists of mixed chimerism induced by an injection of donor spleen and bone marrow cells followed by cyclophosphamide treatment and a donor lymphocyte infusion (DLI), exerted antitumor effects on established murine bladder tumor, MBT-2. An expansion of donor CD4 T cells accompanied by transient but vigorous IFN- production was detected shortly after DLI. Invivo neutralization of IFN- or depletion of CD4 T cells from DLI abolished the antitumor effects, indicating an indispensable role of donor CD4 T cells producing IFN-. Donor as well as host CD8 T cells accumulated in the tumor region with time. Importantly, depletion of CD8 T cells from DLI did not reverse the suppression of tumor growth, indicating that CD4 T cells play a more essential role in mediating early antitumor effects. Furthermore, tumor-specific response of host CD8 T cells was suggested. These results not only provide the first evidence of nonmyeloablative allogeneic SCT for the treatment of bladder tumor but also elucidate detailed mechanisms of antitumor effects provoked by DLI. [Cancer Res 2009;69(12):5151–8]

Key Words: bladder tumor, cyclophosphamide, bone marrow transplantation, GVT, donor lymphocyte infusion