Immunologic alterations in the pancreatic cancer microenvironment of patients treated with neoadjuvant chemotherapy and radiotherapy
Matthew R. Farren, … , Walid Shaib, Gregory B. Lesinski
Matthew R. Farren, … , Walid Shaib, Gregory B. Lesinski
Published January 16, 2020; First published December 12, 2019
Citation Information: JCI Insight. 2020;5(1):e130362. https://doi.org/10.1172/jci.insight.130362.
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Research Article Immunology Oncology

Immunologic alterations in the pancreatic cancer microenvironment of patients treated with neoadjuvant chemotherapy and radiotherapy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has dismal 5-year survival (<9%). We hypothesize that exposure of tumors to conventional therapies may preferentially modulate immune biomarkers in the tumor microenvironment in PDAC. PDAC patients who underwent upfront surgical resection or who received neoadjuvant FOLFIRINOX with or without neoadjuvant radiotherapy followed by surgical resection were selected for study. Total expression of immunologically relevant transcripts and spatially resolved expression of immunologically relevant proteins was quantitated using multiplexed methods (NanoString nCounter and GeoMX platforms). This analysis identified numerous differentially expressed transcripts associated with the type of neoadjuvant therapy received. Moreover, we identified significant alterations in the expression and/or spatial distribution of immunologically relevant proteins in different regions (tumor cell rich, immune cell rich, stromal cell rich) of the tumor microenvironment. These data provide insight into the immunological effects of clinically relevant neoadjuvant therapy for resectable/borderline-resectable PDAC by describing significant differences in the expression of key immunologic biomarkers within the PDAC microenvironment that were associated with the type of treatment patients received prior to surgical resection. This represents a comprehensive analysis of numerous biomarkers conducted on the PDAC microenvironment. This work may guide strategic new combination therapies for pancreatic cancer.

Authors

Matthew R. Farren, Layal Sayegh, Michael Brandon Ware, Hsiao-Rong Chen, Jingjing Gong, Yan Liang, Alyssa Krasinskas, Shishir K. Maithel, Mohammad Zaidi, Juan M. Sarmiento, David Kooby, Pretesh Patel, Bassel El-Rayes, Walid Shaib, Gregory B. Lesinski

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Figure 2

Selection of tumor-rich, immune cell–rich, and stroma-rich regions within PDAC tumors.

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Selection of tumor-rich, immune cell–rich, and stroma-rich regions withi...
As part of GeoMX workflow, FFPE slides of PDAC tumors from patients who received upfront surgical resection or surgical resection following neoadjuvant therapy with either FOLFIRINOX alone or FOLFIRINOX + SBRT were stained with fluorescently labeled anti–pan-cytokeratin (green), anti-CD45 (red), and anti–α-smooth muscle actin (αSMA, blue). A representative slide is shown. These fluorescently labeled antibodies were used to manually define regions of interest with the intent being to select tumor-rich regions (rich in pan-cytokeratin staining but largely lacking CD45 and αSMA staining), immune cell–rich regions (rich in CD45 staining but largely lacking pan-cytokeratin and αSMA staining), and stroma-rich regions (rich in αSMA but largely lacking the other 2 markers). Scale bar: 0.1 cm.