TY - JOUR
T1 - Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception
AU - Hernandez, Sharia
AU - Parra, Edwin Roger
AU - Uraoka, Naohiro
AU - Tang, Ximing
AU - Shen, Yu
AU - Qiao, Wei
AU - Jiang, Mei
AU - Zhang, Shanyu
AU - Mino, Barbara
AU - Lu, Wei
AU - Pandurengan, Renganayaki
AU - Haymaker, Cara
AU - Affolter, Kajsa
AU - Scaife, Courtney L.
AU - Yip-Schneider, Michele
AU - Schmidt, C. Max
AU - Firpo, Matthew A.
AU - Mulvihill, Sean J.
AU - Koay, Eugene J.
AU - Wang, Huamin
AU - Wistuba, Ignacio I.
AU - Maitra, Anirban
AU - Solis, Luisa M.
AU - Sen, Subrata
N1 - Funding Information:
C. Haymaker reports other support from Briacell, as well as personal fees from Nanobiotix outside the submitted work. M. Yip-Schneider reports grants from NIH during the conduct of the study, as well as grants from NIH outside the submitted work. M.A. Firpo reports grants from NIH during the conduct of the study; in addition, M.A. Firpo has a patent 10,451,628 issued. E.J. Koay reports grants from NIH, DOD, SU2C, Elekta, GE Healthcare, Philips Healthcare, and EMD Serono during the conduct of the study, as well as personal fees from RenovoRx, Taylor and Francis LLC, Apollo Health, MD Anderson Physicians Network, and AstraZeneca outside the submitted work. I.I. Wistuba reports grants and personal fees from Genentech/Roche, Bayer, Bristol Myers Squibb, Astra-Zeneca, Pfizer, HTG Molecular, Merck, Guardant Health, Novartis, Sanofi Aventis, and Amgen; personal fees from GlaxoSmithKline, Flame, Daiichi Sankyo, Janssen, Oncocyte, Medscape, Aptitute Health, OncLive, and Platform Health; and grants from Medimmune, 4D, Adaptimmune, Takeda, EMD Serono, Johnson & Johnson, Karus, Iovance, and Akoya outside the submitted work. A. Maitra reports grants from NIH/NCI and MD Anderson Cancer Center during the conduct of the study. A. Maitra also reports other support from Cosmos Wisdom Biotechnology and Thrive Earlier Detection (an Exact Sciences company), as well as personal fees from Freenome and Tezcat Biotech outside the submitted work. S. Sen reports grants from NCI/NIH during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
A. Maitra and S. Sen are supported by U01 CA196403, U01 CA200468, UO1 CA 214263, P50 CA221707, and U24 CA224020. This project was also supported in part by The Translational Molecular Pathology Immunoprofiling Laboratory (TMP-IL) at the Department of Translational Molecular Pathology and the Moonshot Program in Pancreatic Cancer at the University of Texas MD Anderson Cancer Center (Houston, TX). We thank Dr. Arvind Rao and Dr. Souptik Barua
Publisher Copyright:
©2022 The Authors; Published by the American Association for Cancer Research
PY - 2022/5/2
Y1 - 2022/5/2
N2 - 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.
AB - 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.
KW - Adenocarcinoma, Mucinous/pathology
KW - Carcinoma, Pancreatic Ductal/pathology
KW - Humans
KW - Pancreatic Intraductal Neoplasms
KW - Pancreatic Neoplasms/pathology
KW - Tumor Microenvironment
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U2 - 10.1158/1078-0432.CCR-21-2585
DO - 10.1158/1078-0432.CCR-21-2585
M3 - Article
C2 - 35491652
AN - SCOPUS:85129780997
VL - 28
SP - 1938
EP - 1947
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 9
ER -