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JAK-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy
Chunwan Lu1, Asif Talukder2, Natasha M Savage3
1Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA; Georgia Cancer Center, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
Abstract:
Human pancreatic cancer does not respond to immune check point blockade immunotherapy. One key feature of pancreatic cancer is the association between its progression and chronic inflammation. Emerging evidence supports a key role for the JAK-STAT pathway in pancreatic cancer inflammation. We aimed at testing the hypothesis that sustained JAK-STAT signaling suppresses cytotoxic T lymphocyte (CTL) activation to counteract anti-PD-1 immunotherapy-induced CTL activity in pancreatic cancer. We show that human pancreatic carcinomas express high level of PD-L1 and exhibit low level of CTL infiltration. JAK-STAT inhibitor Ruxolitinib selectively inhibits STAT1 and STAT3 activation and increases CTL infiltration to induce a Tc1/Th1 immune response in the tumor microenvironment in an orthotopic pancreatic cancer mouse model. Ruxilitinib-mediated tumor suppressive efficacy diminishes in T-cell-deficient mice. Pancreatic tumor grows significantly faster in IFNγ-deficient mice. However, neutralizing IFNγ does not alter tumor growth but diminishes Ruxolitinib-induced tumor suppression in vivo, indicating that lymphocytes and IFNγ are essential for Ruxolitinib-induced host antitumor immune response. Both type I and type II interferons upregulate PD-L1 expression through the JAK-STAT signaling pathway in mouse pancreatic tumor cells. Tumor cells respond to activated T cells by activating STAT3. The inhibition of STAT3 downregulates immune suppressive cytokines production by tumor cells, resulting in increased T cell activation and effector function. Consequently, Ruxolitinib significantly improves the efficacy of anti-PD-1 immunotherapy. Our data demonstrate that Ruxolitinib is effective in the inhibition of systemic inflammation in the tumor microenvironment and therefore upregulates CTL infiltration and activation to overcome pancreatic cancer resistance to anti-PD-1 immunotherapy.
Insights
Pancreatic cancer resists immunotherapy by activating JAK-STAT signaling, which suppresses T cells. Inhibiting this pathway with Ruxolitinib restores T cell activity, overcoming resistance to anti-PD-1 therapy.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Pancreatic cancer exhibits resistance to immune checkpoint blockade immunotherapy.
- Chronic inflammation and JAK-STAT pathway activation are key features of pancreatic cancer progression.
- Sustained JAK-STAT signaling is hypothesized to suppress cytotoxic T lymphocyte (CTL) activation, counteracting anti-PD-1 immunotherapy.
Purpose of the Study:
- To investigate the role of JAK-STAT signaling in pancreatic cancer's resistance to immunotherapy.
- To determine if inhibiting JAK-STAT signaling can enhance the efficacy of anti-PD-1 immunotherapy in pancreatic cancer.
Main Methods:
- Utilized an orthotopic pancreatic cancer mouse model.
- Administered JAK-STAT inhibitor Ruxolitinib.
- Assessed CTL infiltration, activation, and immune response.
- Evaluated the impact of Ruxolitinib on PD-L1 expression and cytokine production.
- Conducted experiments in T-cell-deficient and IFNγ-deficient mice.
Main Results:
- Ruxolitinib selectively inhibited STAT1 and STAT3 activation, increasing CTL infiltration and promoting a Tc1/Th1 immune response.
- Ruxolitinib's tumor suppressive effects were dependent on T cells and IFNγ.
- Interferons upregulate PD-L1 expression via JAK-STAT signaling in pancreatic tumor cells.
- STAT3 inhibition reduced immunosuppressive cytokines, enhancing T cell activation and effector function.
- Ruxolitinib significantly improved the efficacy of anti-PD-1 immunotherapy.
Conclusions:
- JAK-STAT signaling inhibition is a viable strategy to overcome pancreatic cancer resistance to anti-PD-1 immunotherapy.
- Ruxolitinib effectively reduces tumor microenvironment inflammation, enhancing CTL infiltration and activation.
- Targeting the JAK-STAT pathway can restore anti-tumor immunity in pancreatic cancer.