例如:"lncRNA", "apoptosis", "WRKY"

Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s.

Nat Commun. 2020 Oct 27;11(1):5415
Takaaki Oba 1 , Mark D Long 2 , Tibor Keler 3 , Henry C Marsh 3 , Hans Minderman 4 , Scott I Abrams 5 , Song Liu 2 , Fumito Ito 6
Takaaki Oba 1 , Mark D Long 2 , Tibor Keler 3 , Henry C Marsh 3 , Hans Minderman 4 , Scott I Abrams 5 , Song Liu 2 , Fumito Ito 6
+ et al

[No authors listed]

Author information
  • 1 Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 2 Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 3 Celldex Therapeutics, Inc., Hampton, NJ, USA.
  • 4 Flow & Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 5 Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 6 Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA. fumito.ito@roswellpark.org.

摘要


The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Evidence indicates crucial roles of Batf3-dependent conventional type-1 dendritic cells (cDC1s) for inducing antitumor T-cell immunity; however, strategies to maximize cDC1 engagement remain elusive. Here, using multiple orthotopic tumor mouse models resistant to anti-PD-L1-therapy, we are testing the hypothesis that in situ induction and activation of tumor-residing cDC1s overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1+ Slamf6+ CD8+ T cells, triggers regression not only of primary, but also untreated distant tumors, and renders tumors responsive to anti-PD-L1 therapy. Furthermore, serial in situ immunomodulation (ISIM) reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, and establishes tumor-specific immunological memory. These findings provide new insights into cDC1 biology as a critical determinant to overcome mechanisms of intratumoral T-cell exclusion.