Cellular and molecular gastroenterology and hepatology · 2026
Interleukin 6 Drives Durable T Cell-Mediated Immunity to Pancreatic Cancer.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Arneson-Wissink Paige C, Bartlett Alexandra Q, Mendez Heike, Zhu Xinxia, Levasseur Peter R, Diba Parham, Murthy Namratha Turuvekere Vittala, Dickie Jessica, McWhorter Matthew, Jozic Antony, Eygeris Yulia, Sahay Gaurav, Byrne Katelyn T, Scott Gregory D, Eil Robert, Grossberg Aaron J
Аннотация
BACKGROUND & AIMS: Tumor immune resistance is recognized as a contributor to low survivorship in pancreatic ductal adenocarcinoma (PDAC). The inflammatory cytokine interleukin-6 (IL-6) promotes polarization of CD4 T cell populations away from immune tolerance, and induces differentiation of cytotoxic CD8 T cells. This work aims to test whether IL-6 could stimulate an anti-tumor response in PDAC METHODS: We overexpressed IL-6 in multiple KrasG12D/+, Tp53R172H/+, Pdx1-Cre (KPC) cell lines, which were orthotopically implanted in mice (OT-PDACIL6). We followed mouse survival and measured tumor growth, tumor histology, and plasma IL-6 at 5 and 10 days after tumor implantation. We measured tumor immune cell infiltration via flow cytometry and histology. We used antibody-based T cell depletion and secondary tumor implantation rechallenge to test the dependency of the durable immune reaction on T cells. We use lipid nanoparticle (LNP)-based delivery of IL-6 mRNA to the pancreas as an orthogonal approach for testing the effect of elevated IL-6 in the tumor microenvironment on anti-tumor T cell invasion.
RESULTS: Improved survival occurred in all instances of OT-PDACIL6, with one cell line (KxPxCx) reproducibly resulting in long-term recurrence-free survival. With KxPxCx cells, circulating IL-6 was 100-fold higher in OT-KxPxCxIL6 than in OT-KxPxCxparental mice. Flow cytometry revealed increased T cells and natural killer cells and decreased T regulatory cells, and we observed significantly increased lymphoid aggregates in OT-KxPxXCxIL6 as compared with OT--KxPxCxparental tumors. Antibody-based CD4+ and CD8+ T cell depletion prevented tumor clearance and completely abolished the survival advantage in OT-KxPxCxIL6 mice. The anti-tumor immune response to OT-KxPxCxIL6 rendered mice immune to re-challenge with OT-KxPxCxparental tumors. LNP delivery of IL-6 to the pancreas elevated systemic IL-6 levels ∼50 fold, lowered tumor burden, and increased anti-tumor T cell phenotypes.
CONCLUSIONS: Locally high IL-6 concentrations potently enhance the T cell-mediated anti-tumor response to PDAC.
RESULTS: Improved survival occurred in all instances of OT-PDACIL6, with one cell line (KxPxCx) reproducibly resulting in long-term recurrence-free survival. With KxPxCx cells, circulating IL-6 was 100-fold higher in OT-KxPxCxIL6 than in OT-KxPxCxparental mice. Flow cytometry revealed increased T cells and natural killer cells and decreased T regulatory cells, and we observed significantly increased lymphoid aggregates in OT-KxPxXCxIL6 as compared with OT--KxPxCxparental tumors. Antibody-based CD4+ and CD8+ T cell depletion prevented tumor clearance and completely abolished the survival advantage in OT-KxPxCxIL6 mice. The anti-tumor immune response to OT-KxPxCxIL6 rendered mice immune to re-challenge with OT-KxPxCxparental tumors. LNP delivery of IL-6 to the pancreas elevated systemic IL-6 levels ∼50 fold, lowered tumor burden, and increased anti-tumor T cell phenotypes.
CONCLUSIONS: Locally high IL-6 concentrations potently enhance the T cell-mediated anti-tumor response to PDAC.