American Association for Cancer Research
ccr-23-0535_supplementary_data_1_suppds1.xlsx (27.6 kB)

Supplementary Data 1 from Treatment Response in First-Line Metastatic Pancreatic Ductal Adenocarcinoma Is Stratified By a Composite Index of Tumor Proliferation and CD8 T-Cell Infiltration

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posted on 2023-09-01, 08:21 authored by Gregory L. Beatty, Devora Delman, Jiayi Yu, Mingen Liu, Joey H. Li, Liti Zhang, Jae W. Lee, Renee B. Chang, Nathan Bahary, Eugene P. Kennedy, Andrea Wang-Gillam, Gabriela R. Rossi, Ignacio Garrido-Laguna

DEG Table for Pre vs Post (mRNAseq)



National Institutes of Health (NIH)

Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)

Pancreatic Cancer Action Network (PCAN)



Determinants of treatment outcomes to chemotherapy-based regimens in metastatic pancreatic ductal adenocarcinoma (PDA) remain ill-defined. Our aim was to examine tissue-based correlates of treatment response and resistance using matched baseline and on-treatment biopsies collected from patients with PDA treated in the first-line metastatic setting. Patients with treatment-naïve metastatic PDA were enrolled in a Phase II trial (NCT02077881) investigating gemcitabine plus nab-paclitaxel in combination with indoximod, an orally administered small-molecule inhibitor of the IDO pathway. Baseline and on-treatment biopsies (week 8) of metastatic lesions (88% liver) were collected from a cohort of responders (N = 8) and non-responders (N = 8) based on RECIST v1.1 and examined by multiplex IHC and mRNA sequencing. Treatment altered the transcriptional profile of metastatic lesions with a decrease in tumor cell proliferation independent of treatment response. The antiproliferative response was seen in both basal and classical PDA subtypes. PDA subtype was not associated with survival outcomes; instead, genes involved in immune activation distinguished responders from non-responders. Tumor response was associated with an increase in CD3+ and CD8+ T-cell infiltrates into metastatic lesions. A composite of decreased tumor proliferation in response to treatment and increased CD8 T-cell infiltration in metastatic lesions identified responders and associated with a favorable survival outcome. Our findings suggest that inhibiting cancer cell proliferation alone in PDA is insufficient to produce tumor responses and support a role for tumor-extrinsic mechanisms, such as CD8+ T cells, which combine with the cancer cell proliferation index to define treatment outcomes.

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