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157 A critical role of CD40 and CD70 signaling in cDC1s in expansion and antitumor efficacy of adoptively transferred tumor-specific T cells
  1. Takaaki Oba1,
  2. Toshifumi Hoki1,
  3. Takayoshi Yamauchi1,
  4. Tibor Keler2,
  5. Henry Marsh2,
  6. Xuefang Cao3 and
  7. Fumito Ito1
  1. 1RoswellPark Comprehensive Cancer Center, Buffalo, NY, USA
  2. 2Celldex Therapeutics, Inc., Hampton, NJ, USA
  3. 3University of Maryland, Baltimore, MD, USA


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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