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Addition of losartan to FOLFIRINOX and chemoradiation reduces immunosuppression-associated genes, Tregs and FOXP3+ cancer cells in locally advanced pancreatic cancer

ABSTRACT: Purpose: Adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant losartan on the stromal tumor microenvironment. Experimental Design: We performed a gene expression and immunofluorescence (IF) analysis using archived surgical samples from patients treated with LOS+FFX+CRT (NCT01821729), FFX+CRT (NCT01591733) or surgery upfront, without any neoadjuvant therapy. We also conducted a longitudinal analysis of multiple biomarkers in the plasma of treated patients. Results: In comparison to FFX+CRT, LOS+FFX+CRT downregulated immunosuppression and pro-invasion genes. Overall survival (OS) was associated with DC and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC– and blood vessel-related genes for those treated with LOS+FFX+CRT. Furthermore, losartan induced specific changes in circulating levels of IL-8, sTie2 and TGF-. IF revealed significantly less residual disease in lesions treated with LOS+FFX+CRT. Lastly, patients with a complete/near complete pathological response in the LOS+FFX+CRT-treated group had reduced CD4+FOXP3+ regulatory T cells (Tregs), fewer immunosuppressive FOXP3+ cancer cells (C-FOXP3) and increased CD8+ T cells in PDAC lesions. Conclusions: Adding losartan to FFX+CRT reduced pro-invasion and immunosuppression related genes which were associated with improved survival in patients with LAPC. Lesions from responders in the LOS+FFX+CRT-treated group had reduced Tregs, decreased C-FOXP3 and increased CD8+ T cells. These findings suggest that losartan may potentiate the benefit of FFX+CRT by reducing immunosuppression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222788 | GEO | 2023/02/02

REPOSITORIES: GEO

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Project description:Background: While much progress has been accomplished in the understanding of radiation-induced immune effects in tumors, little is known regarding the mechanisms involved at the tumor draining lymph node (TDLN) level following tumor irradiation. The objective of this retrospective study was to assess the immune and biological changes arising in TDLN upon concurrent chemoradiotherapy of primary non-small cell lung cancer (NSCLC) tumors. Methods: Patients with proved localized (cN0M0) NSCLC, treated by radical surgery plus lymph node dissection with (CRT+) or without (CRT-) neoadjuvant chemoradiotherapy, whereby radiotherapy was targeted on the primary tumor with no significant incidental irradiation of the TDLN station (stations XI or X), were identified. Bulk RNA-Seq of TDLNs was performed and data were analyzed based on differential gene expression (DEG) and gene sets enrichment. Results: Sixteen patients were included and 25 TDLNs were analyzed: 6 patients in the CRT+ group (12 samples) and 10 patients in the CRT- group (13 samples). Overall, 1001 genes were differentially expressed between the two groups (CRT+ and CRT-). Analysis with g-profiler revealed that gene sets associated with antitumor immune response, inflammatory response, hypoxia, angiogenesis, epithelial mesenchymal transition and extra-cellular matrix remodeling were enriched in the CRT+ group, whereas only gene sets associated with B cells and B-cell receptor signaling were enriched in the CRT- group. Unsupervised dimensionality reduction identified two clusters of TDLNs from CRT+ patients, of which one cluster (cluster 1) exhibited higher expression of pathways identified as enriched in the overall CRT+ group in comparison to the CRT- group. In CRT+ cluster 1, 3 out of 3 patients had pathological complete response (pCR) or major complete response (MPR) to neoadjuvant CRT, whereas only 1 out of 3 patients in the other CRT+ cluster (cluster 2) experienced MPR and none exhibited pCR. Finally, pathway comparison to published data from pre-metastatic TDLNs uncovered similarities with CRT+ cluster 1. Conclusion: Neoadjuvant concurrent chemoradiotherapy of the primary tumor in N0 NSCLC patients is associated with distinct microenvironment and immunological patterns in TDLNs as compared to TDLNs from patients with non-irradiated tumors. Our data are in line with studies showing superiority of lymph node sparing irradiation of the primary tumor in the induction of systemic antitumor immunity.

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Addition of losartan to FOLFIRINOX and chemoradiation reduces immunosuppression-associated genes, Tregs and FOXP3+ cancer cells in locally advanced pancreatic cancer

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