Background Adoptive cell therapy (ACT) with antigen-specific CD8+ T cells is a promising approach for treating patients with various solid malignancies including melanoma. In vivo expansion of adoptively transferred T cells is one of the major determinants of successful ACT. On the other hand, a frequently overlooked consideration is that the host antigen-presenting cells affect the antitumor efficacy of ACT. Accumulating evidence suggests that tumor-residing Batf3-dependent conventional type I dendritic cells (cDC1s) play an important role in trafficking of adoptively transferred T cells into the tumor by producing chemokines such as CXCL10, and improve antitumor efficacy of ACT. However, a role of cDC1s in expansion of adoptively transferred T cells remains unclear.
Methods We utilized Pmel-1 T cell receptor transgenic T cells in the B16 melanoma model to investigate the role of cDC1s in expansion of adoptively transferred tumor-specific T cells.
Results While adoptive transfer of in vitro-activated Pmel-1 T cells with vaccination of cognate antigen, hgp100, agonistic anti-CD40 monoclonal antibody (mAb), and Toll-like receptor 7 (TLR7) agonist delayed the tumor growth and survival in wild type C57BL/6 mice (WT), antitumor efficacy of ACT was completely abrogated in Batf3-/- mice. Flow cytometric analysis of peripheral blood showed expansion of adoptively transferred Pmel-1 T cells was significantly compromised in WT mice but not in in Batf3-/- mice. Mechanistically, loss-of-function studies using mixed bone marrow chimera reconstituted with Batf3-/- and CD40-/- (Batf3-/-/CD40-/-), Batf3-/- and CD70-/- (Batf3-/-/CD70-/-), or Batf3-/- and CD80/86-/- (Batf3-/-/CD80/86-/-) revealed CD40-CD70 axis but not CD80/86 signaling in host cDC1s plays an important role in expansion of adoptively transferred T cells. Accordingly, overall survival of Batf3-/-/CD70-/- mixed chimeric was significantly shorter than that of Batf3-/-/WT mice, while survival of Batf3-/-/CD80/86-/- mice was similar to that of Batf3-/-/WT mice. Furthermore, induction of cDC1s by administration of Fms-like tyrosine kinase 3 receptor ligand (gain-of-function) demonstrated significantly enhanced in vivo expansion of adoptively transferred Pmel-1 T cells associated with improved tumor control and survival.
Conclusions These findings elucidate a role of host cDC1s in expansion of adoptively transferred in vivo restimulated tumor-specific T cells, and identify CD40 and CD70 as key molecules.
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