Immune checkpoint receptors and their blockade in skin and gut

/ABSTRACT Immune checkpoint receptor inhibitors (CPIs) have revolutionized cancer care by providing durable therapeutic responses across multiple types of cancer. CPIs boost anti-cancer T cell immunity by blocking and preventing the inhibitory functions of immune checkpoint receptors such as PD-1, CTLA-4, Lag-3, Tigit and Tim-3 that are expressed by cancer-responding T cells as a consequence of activation and exhaustion. However, CPIs are not specific for cancer-responding T cells because many other cell types, including immune and non-immune cells, express checkpoint receptors. Thus, CPIs frequently cause debilitating, sometimes life-threatening, autoimmune-like side effects known as immune-related Adverse Events (irAEs). Depending on regimen, it is calculated that up to 80% of CPI-treated patients develop irAEs, of which cutaneous lichenoid rashes and colitis are the most frequent manifestations. The pathogenesis of irAEs remains unclear, resulting in limited, often unideal, options for the clinical management of patients with irAEs and poor clinical outcomes. Thus, new experimental models of irAEs and irAE-specific therapies are critically needed to develop approaches that prevent or limit the anti-tissue effects of CPIs without negatively interfering with their anti-cancer effects. T cell infiltration and clonal expansion are often seen in affected organs in patients with irAEs, including lichenoid rashes and colitis, suggesting the hypothesis that CPIs cause irAEs by breaking T cell tolerance towards antigens expressed/presented in healthy organs and unleashing a cytotoxic T cell response against such organs. The goal of this proposal is to explore this hypothesis and its underlying mechanisms with innovative mouse models of irAEs and comparative analyses of mouse irAEs vs. human irAE specimens. In Aim 1, we will leverage the “NCR” mouse, where skin-specific antigen expression coupled to blockade of the checkpoint receptor PD-1 leads to localized cytotoxic CD8 T cell-dependent cutaneous pathology with features of human lichenoid irAEs. Here, we will use NCR mice and comparisons with human skin specimens to establish the role of other clinically relevant checkpoint receptors (including Lag-3, Tigit, and Tim-3) in cutaneous tolerance and irAEs. In Aim 2, we will leverage an additional mouse model where we can achieve colon-specific antigen expression and local infiltration of antigen-specific T cells (“NXR” mouse). We will use NXR mice and comparisons with human colon specimens to assess the function and fate of colon-infiltrating T cells and their response to CPIs as a way to establish a model of CPI-induced colitis. In Aim 3, we will implant tumor cell lines into NCR mice or NXR mice to develop a tumor/irAE mouse model where we concomitantly study the transcriptional and functional landscapes of irAE-causing T cells and tumor-responding T cells after CPIs. In conclusion, in this proposal I describe the use of cutting-edge experimental mouse models to elucidate fundamental mechanisms of checkpoint receptor-dependent T cell tolerance in skin and gut, understand irAEs pathogenesis and lay the groundwork for the development of irAE-specific therapies. Project Number: 1R37CA312224-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Martina Damo | Institution: UNIVERSITY OF CHICAGO, CHICAGO, IL | Award Amount: $602,641 | Activity Code: R37 | Study Section: Cellular Immunotherapy of Cancer Study Section[CIC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11344989