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 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 1

Neoadjuvant FOLFIRINOX plus radiotherapy is associated with substantial alterations in immunologically relevant gene expression.

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Neoadjuvant FOLFIRINOX plus radiotherapy is associated with substantial ...
(A) Heat map clustering of gene expression in archival PDAC samples resected from patients who received no neoadjuvant therapy, neoadjuvant FOLFIRINOX, or neoadjuvant FOLFIRINOX plus stereotactic beam radiotherapy or external beam radiotherapy (n = 6 patients/treatment group). Each column represents 1 individual patient tumor, and each row represents 1 gene. Unsupervised hierarchical clustering of genes and samples was carried out by uncentered Pearson correlation. Color indicates normalized counts of each gene, with red representing higher expression and green relatively lower expression. (B) Venn diagram indicating how many differentially expressed genes were found in each comparison and how many genes overlapped each set of comparisons. FS-C, F + SBRT versus surgery alone; FX-C, F + XRT versus surgery alone; FS-F, F + SBRT versus FOLFIRINOX; FX-F, F + XRT versus FOLFIRINOX. (C–G) Volcano plots depicting differentially expressed gene P value as a function of fold change between the indicated groups. Red dots indicate FDR-adjusted P value of less than 0.05. (C) DEGs in FOLFIRINOX-treated vs. surgery-alone tumors. (D) DEGs in F + SBRT–treated vs. surgery-alone tumors. (E) DEGs in F + XRT–treated vs. surgery-alone tumors. (F) DEGs in F + SBRT–treated versus FOLFIRINOX-treated tumors. (G) DEGs in F + XRT–treated versus FOLFIRINOX-treated tumors.