Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA

Area of Science:

• Immunology
• Cancer Research
• Pharmacology

Background:

• V-domain Ig Suppressor of T cell Activation (VISTA) is a key immune checkpoint target in cancer immunotherapy.
• Blocking VISTA activates innate and adaptive immunity, showing potential for tumor eradication.
• VISTA is expressed on myeloid and lymphoid cells, influencing T cell responses.

Purpose of the Study:

• To evaluate the efficacy of a VISTA antagonist, CA170, as a cancer immunotherapy.
• To investigate the combined effect of CA170 and a KRAS peptide vaccine on lung tumorigenesis.
• To elucidate the immunoregulatory mechanisms underlying the combination therapy.

Main Methods:

• Carcinogen-induced mouse lung tumorigenesis model.
• Administration of VISTA antagonist CA170 and/or MHCII-directed KRAS peptide vaccine.
• Flow cytometry and single-cell RNA sequencing (scRNA-seq) for immune cell analysis.

Main Results:

• CA170 demonstrated potent anticancer efficacy in mouse lung tumors.
• Combination therapy of CA170 and KRAS vaccine almost completely suppressed lung tumor development.
• CA170 increased CD8+ T cell infiltration and effector functions by reducing myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells.
• KRAS vaccine induced CD4+ effector T cell expansion.

Conclusions:

• VISTA antagonism by CA170 is effective against lung tumorigenesis.
• The combination therapy drives a tumor-specific adaptive T cell immune response.
• This approach broadly modulates immune cells, enhancing the efficacy of KRAS-targeted vaccines.