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Mechanistic Insights into Proglumide's Role in Immune Cell Efficacy and Response to Immune Checkpoint Inhibitor
Priyanka S Doneparthi1, Hong Cao2, Wenqiang Chen2
1Department of Oncology, Georgetown University, Washington, DC 20007, USA.
Background:
New strategies are needed to improve the response to immune checkpoint inhibitors for the treatment of hepatocellular carcinoma.
Methods:
Mice bearing HCC tumors were treated with PBS (control), a PD-1 antibody (PD-1Ab), proglumide, or the combination of proglumide and the PD-1Ab. The tumor microenvironment (TME) was evaluated histologically for fibrosis and by immunohistochemistry for immune cells. To investigate the mechanisms involved in T-cell efficiency, mouse spleen cells were isolated and examined for T-cell exhaustion markers and cytokine release. The mouse microbiome was analyzed using whole-genome sequencing before therapy and at the end of the study.
Results:
The combination of proglumide with a PD-1Ab decreased tumoral fibrosis better than monotherapy, and altered the immune cell signature in the TME by decreasing M2-polarized macrophages and increasing the influx of CD8+ T-cells. Proglumide monotherapy or in combination with the PD-1Ab decreased T-cell exhaustion markers and improved cytokine release. The combination therapy resulted in changes to the microbiome, including increased beneficial bacteria and genera known to enhance the efficacy of ICIs.
Conclusions:
Co-administration of proglumide with ICIs resulted in remodeling of the TME, changing a "cold" tumor to a "hot" immune-responsive tumor, activating T-cells, and altering the host microbiome to a population of bacteria that are beneficial.
Insights
Combining proglumide with PD-1 antibody therapy enhances immune checkpoint inhibitor (ICI) efficacy for hepatocellular carcinoma (HCC). This approach remodels the tumor microenvironment, activates T-cells, and promotes beneficial gut bacteria.
Area of Science:
- Immunotherapy
- Oncology
- Microbiome Research
Background:
- Hepatocellular carcinoma (HCC) exhibits poor response to immune checkpoint inhibitors (ICIs).
- Novel strategies are required to enhance ICI effectiveness in HCC treatment.
Purpose of the Study:
- To investigate the efficacy of combining proglumide with a PD-1 antibody in a preclinical HCC model.
- To elucidate the effects of this combination therapy on the tumor microenvironment, T-cell function, and gut microbiome.
Main Methods:
- Mice with HCC tumors were treated with PBS, PD-1 antibody, proglumide, or combination therapy.
- Tumor microenvironment (TME) analysis included fibrosis assessment and immune cell profiling.
- T-cell exhaustion markers and cytokine release were measured.
- Whole-genome sequencing was used for microbiome analysis.
Main Results:
- Combination therapy significantly reduced tumoral fibrosis and modulated the TME by decreasing M2 macrophages and increasing CD8+ T-cells.
- Proglumide, alone or combined, reduced T-cell exhaustion and improved cytokine production.
- Combination therapy altered the microbiome, increasing beneficial bacteria associated with enhanced ICI efficacy.
Conclusions:
- Co-administration of proglumide with ICIs converts "cold" tumors to "hot" immune-responsive tumors.
- The combination therapy activates T-cells and beneficially alters the host microbiome.
- This strategy shows promise for improving HCC treatment outcomes.
