Requirement of the acquired immune system in successful cancer chemotherapy with cis-diamminedichloroplatinum (II) in a syngeneic mouse tumor transplantation model.

We examined the involvement of acquired immune response in the therapeutic effect of systemic tumor chemotherapy with cis-diamminedichloroplatinum (II) (cis-DDP) using a mouse syngeneic cancer transplantation model. The therapeutic effect observed in BALB/c mice was negligible in athymic BALB/c mice. The therapeutic effect became obvious when athymic mice were immunologically reconstituted with splenocytes containing CD4 T cells of BALB/c mice. The BALB/c mice in which tumor chemotherapy was successful exhibited cell line-specific tumor immunity to the second tumor transplantation. Splenocytes of these mice exhibited cell line-specific cytotoxicity. After systemic cis-DDP treatment, an increase in apoptotic cells and macrophage infiltration was observed in the tumor mass. In the same lesion, an increase in the levels of high-mobility group box protein and its intracellular translocation from the nucleus to the cytoplasm were observed. In a chase study on the infiltrated macrophage with labeled tumor cells, the translocation of tumor cell components to regional lymph nodes was observed after the chemotherapy. The peripheral monocytosis induced by administrations of monocyte colony-stimulating factor augmented the therapeutic efficacy of cis-DDP treatment. These indicate that the phagocytosis of apoptotic tumor cells exhibiting the adjuvant protein by infiltrated macrophages and the subsequent antigen presentation by the macrophages to T cells take place, and that the acquired immune response to the tumor cells as the consequence plays an essential role in the therapeutic effect of cis-DDP.