Chemotherapy in Synergy With Innate Immune Agonists Enhances T Cell Priming for Checkpoint Inhibitor Treatment in Pancreatic Cancer

Authors

Nan Niu
Keyu Li
Junke Wang
Vanessa Funes
Birginia Espinoza
Pan Li
Jianxin Wang
Melissa Lyman
Mengni He
Brian Herbst
Michael Wichroski
Ruslan Novosiadly
Sami Shoucair
Yiping Mou
Lei Zheng

Publication Date

1-27-2025

Journal

Biomarker Research

Abstract

Background: The combination of conventional chemotherapy and immune checkpoint inhibitors (ICIs) has been unsuccessful for pancreatic ductal adenocarcinoma (PDAC). Administration of maximum tolerated dose of chemotherapy drugs may have immunosuppressive effects.

Methods: We thus tested, by using the preclinical model of PDACs including the genetically engineered mouse KPC spontaneous pancreatic tumor model and the pancreatic KPC tumor orthotopic implant model, the combinations of synthetic innate immune agonists including STING and NLRP3 agonist, respectively, and ICIs with or without chemotherapy.

Results: We found that innate agonists potentiate the role of chemotherapy in inducing effector T cells and subsequently to prime the tumor microenvironment (TME) better for ICI treatments. Triple combination of chemotherapy, innate agonists, and ICIs is superior to single modalities or double modalities in antitumor efficacies. Adding chemotherapy to innate agonists enhances the infiltration of overall CD8+ T cells and the memory cytotoxic subtype. NLRP3 agonist has a less effect than STING agonist on driving the T cell exhaustion. Adding chemotherapy to innate agonists enhances the infiltration of dendritic cells (DCs) in the tumors and CD86+ mature DCs in tumor draining lymph nodes. RNA sequencing analysis of the pancreatic tumors demonstrates the role of the combination of STING/NLRP3 agonist and chemotherapy, but not either treatment modality alone, in upregulating the T cell activation signaling. The NLRP3 agonist-mediated T cell activation is likely through regulating the nitrogen metabolism pathways.

Conclusion: This study supports the clinical testing of both STING and NLRP3 agonists, respectively, in combination with chemotherapy to sensitize PDAC patients for ICI treatments.

Keywords

Chemotherapy, Immune checkpoint inhibitors, Innate immune agonists, NLRP3 agonist, Pancreatic ductal adenocarcinoma, STING agonist, Tumor microenvironment.

DOI

10.1186/s40364-024-00721-7

PMID

39871312

PMCID

PMC11773940

PubMedCentral® Posted Date

1-27-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes