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DPP Inhibition Enhances the Efficacy of PD-1 Blockade by Remodeling the Tumor Microenvironment in Lewis Lung
Mengrong Lei1,2, Junyan Liu3, Ying Gao1,2
1Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
Abstract:
The remarkable efficacy of cancer immunotherapy has been established in several tumor types. Of the various immunotherapies, PD-1/PD-L1 inhibitors are most extensively used in the treatment of many cancers in clinics. These inhibitors restore the suppressed antitumor immune response and inhibit tumor progression by blocking the PD-1/PD-L1 signaling. However, the low response rate is a major limitation in the clinical application of PD-1/PD-L1 inhibitors. Therefore, combination strategies that enhance the response rate are the need of the hour. In this investigation, PT-100 (also referred to as Talabostat, Val-boroPro, and BXCL701), an orally administered and nonselective dipeptidyl peptidase inhibitor, not only augmented the effectiveness of anti-PD-1 therapy but also significantly improved T immune cell infiltration and reversed the immunosuppressive tumor microenvironment. The combination of PT-100 and anti-PD-1 antibody increased the number of CD4+ and CD8+ T cells. Moreover, the mRNA expression of T cell-associated molecules was elevated in the tumor microenvironment. The results further suggested that PT-100 dramatically reduced the ratio of tumor-associated macrophages. These findings provide a promising combination strategy for immunotherapy in lung cancer.
Insights
Combining PT-100 with anti-PD-1 therapy shows promise for lung cancer. This approach enhances T cell activity and reverses the immunosuppressive tumor microenvironment, improving immunotherapy response rates.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Cancer immunotherapy, particularly PD-1/PD-L1 inhibitors, has shown efficacy but suffers from low response rates.
- Combination strategies are crucial to overcome limitations and enhance clinical outcomes in cancer treatment.
- The tumor microenvironment plays a critical role in immune evasion and treatment resistance.
Purpose of the Study:
- To investigate the efficacy of combining PT-100 (Talabostat) with anti-PD-1 therapy in a preclinical cancer model.
- To evaluate the impact of this combination on T cell infiltration and the tumor microenvironment.
- To determine if PT-100 can enhance the effectiveness of PD-1/PD-L1 blockade.
Main Methods:
- Utilized PT-100, an orally administered dipeptidyl peptidase inhibitor, in combination with an anti-PD-1 antibody.
- Assessed T cell infiltration (CD4+ and CD8+) within the tumor microenvironment.
- Analyzed mRNA expression of T cell-associated molecules and the ratio of tumor-associated macrophages.
Main Results:
- The combination of PT-100 and anti-PD-1 therapy significantly augmented anti-tumor immune responses.
- Increased infiltration of CD4+ and CD8+ T cells was observed in the tumor microenvironment.
- PT-100 demonstrated a reduction in immunosuppressive tumor-associated macrophages and elevated T cell-associated gene expression.
Conclusions:
- The combination of PT-100 and anti-PD-1 antibody represents a promising strategy to enhance cancer immunotherapy.
- This combination effectively reverses the immunosuppressive tumor microenvironment and boosts T cell-mediated anti-tumor immunity.
- This approach holds potential for improving treatment outcomes in lung cancer and potentially other malignancies.
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