TY - JOUR
T1 - Rintatolimod in Advanced Pancreatic Cancer Enhances Antitumor Immunity through Dendritic Cell–Mediated T-Cell Responses
AU - van Eijck, Casper H.J.
AU - Haddaoui, Hassana El
AU - Kucukcelebi, Songul
AU - Vadgama, Disha
AU - Fellah, Amine
AU - Mustafa, Dana A.M.
AU - Aerts, Joachim G.J.V.
AU - van Eijck, Casper H.J.
AU - Willemsen, Marcella
N1 - Publisher Copyright:
©2024 American Association for Cancer Research.
PY - 2024/8/15
Y1 - 2024/8/15
N2 - Purpose: Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a Toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the antitumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of patients with advanced PDAC. Experimental Design: Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunologic factors on survival outcomes was assessed through univariate Cox proportional hazards models. Results: Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+ XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pro-nouncedDCand T-cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1. Conclusions: This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunologic tolerance by enhancing antitumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes.
AB - Purpose: Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a Toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the antitumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of patients with advanced PDAC. Experimental Design: Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunologic factors on survival outcomes was assessed through univariate Cox proportional hazards models. Results: Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+ XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pro-nouncedDCand T-cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1. Conclusions: This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunologic tolerance by enhancing antitumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes.
UR - http://www.scopus.com/inward/record.url?scp=85196948239&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-23-4085
DO - 10.1158/1078-0432.CCR-23-4085
M3 - Article
C2 - 38488815
AN - SCOPUS:85196948239
SN - 1078-0432
VL - 30
SP - 3447
EP - 3458
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -
