Mechanistic Insights into Proglumide's Role in Immune Cell Efficacy and Response to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma.

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.