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

Takaaki Oba, Mark D. Long, Tibor Keler, Henry C. Marsh, Hans Minderman, Scott I. Abrams, Song Liu and Fumito Ito ()
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Takaaki Oba: Roswell Park Comprehensive Cancer Center
Mark D. Long: Roswell Park Comprehensive Cancer Center
Tibor Keler: Celldex Therapeutics, Inc.
Henry C. Marsh: Celldex Therapeutics, Inc.
Hans Minderman: Roswell Park Comprehensive Cancer Center
Scott I. Abrams: Roswell Park Comprehensive Cancer Center
Song Liu: Roswell Park Comprehensive Cancer Center
Fumito Ito: Roswell Park Comprehensive Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19192-z

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