Diminished Immune Surveillance During Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception

Authors

Sharia Hernandez
Edwin Roger Parra
Naohiro Uraoka
Ximing Tang
Yu Shen
Wei Qiao
Mei Jiang
Shanyu Zhang
Barbara Mino
Wei Lu
Renganayaki Pandurengan
Cara Haymaker
Kajsa Affolter
Courtney L Scaife
Michele Yip-Schneider
C Max Schmidt
Matthew A Firpo
Sean J Mulvihill
Eugene J Koay
Huamin Wang
Ignacio I Wistuba
Anirban Maitra
Luisa M Solis
Subrata Sen

Publication Date

5-2-2022

Journal

Clinical Cancer Research

Abstract

Purpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses.

Experimental design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology-related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set.

Results: Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression.

Conclusions: Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.

Keywords

Adenocarcinoma, Mucinous, Carcinoma, Pancreatic Ductal, Humans, Pancreatic Intraductal Neoplasms, Pancreatic Neoplasms, Tumor Microenvironment

DOI

10.1158/1078-0432.CCR-21-2585

PMID

35491652

PMCID

PMC9069801

PubMedCentral® Posted Date

2-23-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes