CD40 Ligand Promotes Priming of Fully Potent Antitumor CD4+ T Cells in Draining Lymph Nodes in the Presence of Apoptotic Tumor Cells

• Published in: The Journal of immunology (1950) 2001-11, Vol.167 (10), p.5678-5688
• Main Authors: Fujita, Nanae, Kagamu, Hiroshi, Yoshizawa, Hirohisa, Itoh, Kazuhisa, Kuriyama, Hideyuki, Matsumoto, Naoya, Ishiguro, Takuro, Tanaka, Junta, Suzuki, Eiichi, Hamada, Hirofumi, Gejyo, Fumitake
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Brain Neoplasms - immunology; Brain Neoplasms - therapy; Cancer Vaccines; CD40 Ligand - genetics; CD40 Ligand - physiology; Cells, Cultured; Dendritic Cells - immunology; Female; Immunotherapy, Adoptive; Interleukin-2 - biosynthesis; L-Selectin - analysis; Lymph Nodes - immunology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - transplantation; Mice; Mice, Inbred C57BL; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Neoplasms, Experimental - therapy; Survival Rate; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - transplantation; Th1 Cells - immunology; Transduction, Genetic
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.10.5678

The presence or absence of CD4(+) T cell help can determine the direction of adaptive immune responses toward either cross-priming or cross-tolerance. It has been demonstrated that interactions of CD40-CD40 ligand can replace CD4(+) T cell help and enable dendritic cells to prime cytotoxic T cells. Here, we demonstrate that antitumor reactivity induced in regional lymph nodes (LNs) by s.c. injection of CD40 ligand (CD40L)-transduced tumor (MCA205 CD40L) showed far superior therapeutic efficacy against established brain tumors of a weakly immunogenic fibrosarcoma, MCA205, when adoptively transferred. Coinjection of apoptotic, but not necrotic parental tumor cells with CD40L-expressing tumor cells caused a strong synergistic induction of antitumor reactivity in tumor-draining LNs. Freshly isolated T cells from LNs immunized with apoptotic parental tumor cells and MCA205 CD40L were capable of mediating regression of the parental tumor in vivo. In contrast, T cells derived from LNs immunized without MCA205 CD40L required ex vivo anti-CD3/IL-2 activation to elicit therapeutic activity. On anti-CD3/IL-2 activation, cells from LNs immunized with MCA205 CD40L exhibited superior per cell antitumor reactivity. An in vitro depletion study revealed that either CD4(+) or CD8(+) T cells could mediate therapeutic efficacy but that the antitumor efficacy mediated by CD4(+) T cells was far superior. Cytosolic flow cytometric analyses indicated that priming of CD4(+) cells in LNs draining CD40L-expressing tumors was polarized to the Th1 type. This is the first report that fully potent antitumor CD4(+) T cell priming was promoted by s.c. injection of CD40L-transduced tumor in the presence of apoptotic tumor cells.