VISTA inhibitor CA170 combined with KRAS vaccine enhances immune response in lung cancer

Lung cancer is the leading cause of cancer-related death globally. Immune checkpoint inhibitors (ICI) have emerged as a promising therapy for late-stage lung cancer. However, their response rate remains low, highlighting the need to explore diverse intervention pathways to optimize antitumor efficacy. CA170, a small molecule targeting immune checkpoints Programmed Cell Death Protein 1 (PD-1) and V-domain Ig Suppressor of T cell Activation (VISTA), is highly expressed in the lungs and offers an advantage over antibody-based ICIs due to its membrane permeability. We hypothesized that a combination therapy of CA170, an antigen-independent small molecule, and KRAS vaccine (Kvax), an antigen-specific vaccine targeting the Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in lung cancer, would promote antitumor immune response pathways more strongly than either treatment alone. To test this hypothesis, we analyzed publicly available single-cell RNA sequencing (scRNA-seq) data to examine the effects of the treatment on immune cell compartments. We evaluated immune cell response pathways identified through receptor-ligand analysis via CellChat. Our findings indicate that the combination therapy of CA170 and Kvax enhances helper T cell function and improves cytotoxic T lymphocyte infiltration, while Kvax alone drives plasma and memory B cell proliferation. This study suggests that combining antigen-specific vaccines and antigen-independent ICIs may enhance the antitumor response in lung cancer. Our findings could aid in developing more effective strategies to extend the efficacy of immunotherapy in lung cancer patients.