Local Depletion of Immune Checkpoint Ligand CTLA4 Expressing Cells in Tumor Beds Enhances Antitumor Host Immunity

Abstract

Near-infrared photoimmunotherapy (NIR-PIT) is a cancer treatment that utilizes antibody-photoabsorber (IR700) conjugates to selectively kill target cells by exposing them to NIR light. Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a major immune checkpoint ligand mediating antitumor immune suppression. Local depletion of CTLA4 expressing cells in the tumor bed with NIR-PIT could enhance antitumor immune responses by both blocking the CTLA4-axis and depleting immune suppressive cells. The aim of this study is to evaluate the antitumor efficacy of CTLA4-targeted NIR-PIT using four murine tumor models, MC38-luc, LL/2-luc, MOC2-luc, and MOC2. The CTLA4-targeted NIR-PIT depletes intratumoral CTLA4 expressing cells which are mostly regulatory T cells. <i>In vivo</i> CTLA4-targeted NIR-PIT yields complete responses in 80% of MC38-luc, 70% of LL/2-luc and 40% of MOC2-luc tumors prolonging survival in all cases. After CTLA4-targeted NIR-PIT, activation and infiltration of CD8⁺ T cells within the tumor microenvironment is observed. In conclusion, CTLA4-targeted NIR-PIT can effectively treat tumors by blocking the CTLA4-axis as well as by eliminating CTLA4-expressing immune suppressor cells, resulting in T cell mediated antitumor immunity. Local CTLA4-expressing cell depletion in tumor beds using NIR-PIT could be a promising new cancer immunotherapy for safely treating a variety of tumor types.