Funding
National Institute of Allergy and Infectious Diseases (NIAID)
United States Department of Health and Human Services
Find out more...National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...Hale Family Center for Pancreatic Cancer Research (Hale Family Research Center At Dana-Farber Cancer Institute)
Ludwig Center at Harvard (Ludwig Center)
Cancer Research Institute (CRI)
Pew Charitable Trusts (PCT)
University of Virginia (UV)
Pancreatic Cancer Action Network (PCAN)
Lustgarten Foundation (The Lustgarten Foundation)
Stand Up To Cancer (SU2C)
ARTICLE ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease in which bulky tumor burden and limited time to develop antitumor T cells may have contributed to poor clinical efficacy. Here, we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti–PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors.
We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor.
PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T-cell clonotypes observed in the tumor.
Cytotoxic T cells in the blood of patients with PDAC remain sensitive to reinvigoration by PD-1 blockade, and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti–PD-1 reinvigoration and marks these T cells as non-productive contributors to antitumor immunity.See related commentary by Lander and DeNardo, p. 474
