Pre-treatment inflamed tumor immune microenvironment is associated with FOLFIRINOX response in pancreatic cancer

Zachary Gao; Sung Wook Kang; Derek Erstad; Joseph Azar; George Van Buren; William Fisher; Zequn Sun; Mark P Rubinstein; Hyun-Sung Lee; E Ramsay Camp

doi:10.3389/fonc.2023.1274783

Pre-treatment inflamed tumor immune microenvironment is associated with FOLFIRINOX response in pancreatic cancer

Front Oncol. 2023 Nov 23:13:1274783. doi: 10.3389/fonc.2023.1274783. eCollection 2023.

Authors

Zachary Gao¹, Sung Wook Kang^{1

2

3}, Derek Erstad^{1

2

4}, Joseph Azar⁵, George Van Buren^{1

2}, William Fisher^{1

2}, Zequn Sun⁶, Mark P Rubinstein⁵, Hyun-Sung Lee^{1

2

3}, E Ramsay Camp^{1

2

4}

Affiliations

¹ Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States.
² Department of Surgery, Dan L. Duncan Comprehensive Cancer Center, Houston, TX, United States.
³ Systems Onco-Immunology Laboratory, David J. Sugarbaker Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States.
⁴ Department of Surgery, Michael E. DeBakey VA Medical Center, Houston, TX, United States.
⁵ The Pelotonia Institute for Immuno-Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, United States.
⁶ Department of Preventative Medicine, Northwestern University Clinical and Translational Sciences Institute, Chicago, IL, United States.

Abstract

Introduction: Pancreatic adenocarcinoma (PDAC) is an aggressive tumor with limited response to both chemotherapy and immunotherapy. Pre-treatment tumor features within the tumor immune microenvironment (TiME) may influence treatment response. We hypothesized that the pre-treatment TiME composition differs between metastatic and primary lesions and would be associated with response to modified FOLFIRINOX (mFFX) or gemcitabine-based (Gem-based) therapy.

Methods: Using RNAseq data from a cohort of treatment-naïve, advanced PDAC patients in the COMPASS trial, differential gene expression analysis of key immunomodulatory genes in were analyzed based on multiple parameters including tumor site, response to mFFX, and response to Gem-based treatment. The relative proportions of immune cell infiltration were defined using CIBERSORTx and Dirichlet regression.

Results: 145 samples were included in the analysis; 83 received mFFX, 62 received Gem-based therapy. Metastatic liver samples had both increased macrophage (1.2 times more, p < 0.05) and increased eosinophil infiltration (1.4 times more, p < 0.05) compared to primary lesion samples. Further analysis of the specific macrophage phenotypes revealed an increased M2 macrophage fraction in the liver samples. The pre-treatment CD8 T-cell, dendritic cell, and neutrophil infiltration of metastatic samples were associated with therapy response to mFFX (p < 0.05), while mast cell infiltration was associated with response to Gem-based therapy (p < 0.05). Multiple immunoinhibitory genes such as ADORA2A, CSF1R, KDR/VEGFR2, LAG3, PDCD1LG2, and TGFB1 and immunostimulatory genes including C10orf54, CXCL12, and TNFSF14/LIGHT were significantly associated with worse survival in patients who received mFFX (p = 0.01). There were no immunomodulatory genes associated with survival in the Gem-based cohort.

Discussion: Our evidence implies that essential differences in the PDAC TiME exist between primary and metastatic tumors and an inflamed pretreatment TiME is associated with mFFX response. Defining components of the PDAC TiME that influence therapy response will provide opportunities for targeted therapeutic strategies that may need to be accounted for in designing personalized therapy to improve outcomes.

Keywords: CIBERSORT2; FOLFIRINOX3; PDACpancreatic ductal adenocarcinoma1; RNA sequencing5; immunomodulator(s)4.

Abstract

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