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Updated: May 15, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models
Jian Ye1,2, Shuyang S Qin1,3, Angela L Hughson1,2
1Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
Background:
Recent preclinical and clinical data suggest that leukemia inhibitory factor (LIF) is a potential target for various tumor types including pancreatic ductal adenocarcinoma as LIF is involved in multiple protumor processes including cancer stem cell maintenance, epithelial-mesenchymal transition (EMT), immunosuppression, and chemo/radioresistance. Anti-LIF antibody therapy has demonstrated safety and tolerability but limited efficacy in phase 1 clinical trial in advanced solid tumors. This prompted us to explore combination therapies, suggesting that LIF blockade, when combined with standard-of-care chemotherapy, radiotherapy, and/or immunotherapy, could present a promising therapeutic strategy.
Methods:
We evaluated the impact of combining systemic inhibition of LIF/programmed death-ligand 1 (PD-L1) with localized stereotactic body radiotherapy (SBRT) on tumor progression across multiple murine orthotopic pancreatic tumor models and examined systemic antitumor immunity using a hepatic rechallenge model. The antitumor immune response was characterized throughflow cytometry and Luminex assays. To identify differentially expressed genes and signaling pathways following treatment, we performed bulk RNA sequencing on pancreatic tumors. Additionally, single-cell RNA sequencing was conducted to further examine changes in tumor-infiltrating immune cells and their signaling pathways.
Results:
We showed that simultaneous inhibition of LIF and PD-L1 significantly amplified the antitumor efficacy of SBRT, resulting in extended survival. The triple therapy (SBRT+anti-LIF+anti-PD-L1) generated an immunostimulatory tumor microenvironment, characterized by a proinflammatory shift in the cytokine/chemokine profile, increased infiltration of effector CD8+ T cells, and upregulated activation or maturation signals in tumor-infiltrating CD8+ T cells and macrophages. The beneficial effects of triple therapy were mostly abrogated by depletion of CD8+ T cells. In addition, triple therapy downregulated pathways related to tumor stemness, proliferation, and metabolism, and reduced EMT. Importantly, the combination of local SBRT treatment with systemic LIF and PD-L1 blockade resulted in long-term systemic antitumor memory.
Insights
Combining anti-leukemia inhibitory factor (LIF) and anti-programmed death-ligand 1 (PD-L1) therapies with stereotactic body radiotherapy (SBRT) enhances antitumor immunity and survival in pancreatic cancer models. This triple therapy establishes long-term systemic antitumor memory.
Area of Science:
- Oncology
- Immunology
- Cancer Therapeutics
Background:
- Leukemia inhibitory factor (LIF) promotes pancreatic ductal adenocarcinoma progression via cancer stem cell maintenance, EMT, immunosuppression, and resistance.
- Anti-LIF antibody therapy shows safety but limited efficacy as a monotherapy.
- Combination therapies involving LIF blockade offer a promising strategy.
Purpose of the Study:
- To evaluate the efficacy of combining systemic LIF/PD-L1 inhibition with localized SBRT in pancreatic cancer models.
- To investigate the impact of this triple therapy on tumor progression and systemic antitumor immunity.
Main Methods:
- Murine orthotopic pancreatic tumor models were treated with SBRT, anti-LIF, and anti-PD-L1.
- Tumor progression and systemic immunity were assessed using hepatic rechallenge models.
- Immune responses were characterized by flow cytometry, Luminex assays, bulk and single-cell RNA sequencing.
Main Results:
- Triple therapy (SBRT+anti-LIF+anti-PD-L1) significantly improved survival and amplified antitumor efficacy.
- This combination induced an immunostimulatory tumor microenvironment, increasing CD8+ T cell infiltration and activation.
- Triple therapy reduced tumor stemness, proliferation, metabolism, and EMT, with CD8+ T cell depletion abrogating benefits.
- Long-term systemic antitumor memory was established.
Conclusions:
- Combined SBRT with systemic LIF and PD-L1 blockade is a potent strategy against pancreatic cancer.
- The therapy enhances antitumor immunity, reduces tumor-promoting pathways, and establishes durable immune memory.
- This approach holds significant potential for improving pancreatic cancer treatment outcomes.
