Targeting T Cell Checkpoints 41BB and LAG3 and Myeloid Cell CXCR1/CXCR2 Results in Antitumor Immunity and Durable Response in Pancreatic Cancer

Authors

Pat Gulhati
Aislyn Schalck
Shan Jiang
Xiaoying Shang
Chang-Jiun Wu
Pingping Hou
Sharia Hernandez Ruiz
Luisa Solis Soto
Edwin Parra
Haoqiang Ying
Jincheng Han
Prasenjit Dey
Jun Li
Pingna Deng
Emi Sei
Dean Y Maeda
John A Zebala
Denise J Spring
Michael Kim
Huamin Wang
Anirban Maitra
Dirk Moore
Karen Clise-Dwyer
Y Alan Wang
Nicholas E Navin
Ronald A DePinho

Publication Date

1-1-2023

Journal

Nature Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and to identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and antitumor immunity, characterized by modulating T cell subsets with antitumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the expression of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and the availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease.

Keywords

Humans, Carcinoma, Pancreatic Ductal, Myeloid Cells, Pancreatic Neoplasms, T-Lymphocyte Subsets, Receptors, Interleukin-8A

Comments

Supplementary Materials

PMID: 36585453