Related Experiment Video
Updated: Jul 16, 2025
Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients
Lestat R Ali1,2,3, Patrick J Lenehan1,2, Victoire Cardot-Ruffino1,2
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Purpose:
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.
Experimental Design:
We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor.
Results:
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.
Conclusions:
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.
Insights
Pancreatic cancer patients
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has shown poor response to immune checkpoint inhibitors.
- Tumor burden and limited T cell activation time may hinder efficacy in advanced PDAC.
- Investigating T cell responses to PD-1 blockade in PDAC is crucial.
Purpose of the Study:
- To evaluate the impact of PD-1 blockade on T cells in PDAC patients receiving neoadjuvant therapy.
- To determine if PD-1 blockade reactivates T cells in blood and/or tumor.
- To understand if reactivated T cells explain the clinical benefit or lack thereof.
Main Methods:
- Single-cell transcriptional profiling.
- TCR clonotype tracking to identify blood-tumor T cell matches.
- Analysis of T cell activation and signaling pathways.
Main Results:
- PD-1 blockade increased T cell cycling and IFNγ signature, similar to other GI cancers.
- Reactivated T cells showed significant NF-κB signaling, unlike in responders.
- Newly cycling T cells in blood matched activated T cells found in tumors.
Conclusions:
- Cytotoxic T cells in PDAC are sensitive to PD-1 blockade and can recognize tumors.
- T cell proliferation and IFN exposure were observed, but NF-κB signaling may counteract benefits.
- PD-1 blockade may lead to non-productive T cell responses in PDAC.
More Related Videos
Related Concept Videos
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...
01:24Chronic Pancreatitis I: Introduction
Pancreatitis is the inflammation of the pancreas, which occurs when the immune system becomes active and causes swelling, pain, and disruptions in organ function. Pancreatitis can manifest as either an acute or chronic condition.
Acute pancreatitis arises suddenly and lasts for a brief duration, while chronic pancreatitis is a long-term affliction...
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...