Liver metastasis limits immunotherapy efficacy by dismantling systemic anti-tumor T cell responses through unconventional antigen presentation

Introduction/Rationale: Liver is a well-known site of peripheral immune tolerance induction. Because it processes antigen-rich blood from the gut, the liver has evolved mechanisms to limit over-reaction to food and commensal antigens. When cancer metastasizes to liver, it likely hijacks this tolerogenic function, leading to tolerance to tumor antigens. This tolerance can systemically dampen anti-tumor immunity allowing the cancer to spread and jeopardizing responses to immunotherapy. This is a significant clinical problem as liver is a common site of metastasis. Despite this, liver metastases are treated with the same regimens as other visceral metastases. A significant knowledge gap exists regarding how this tolerance is induced and how it can be reversed.

Methods: To understand the process of liver induced immune tolerance to tumor antigens, we have established a model demonstrating that the presence of liver metastasis suppresses antigen specific anti-tumor immune responses systemically.

Results: We found that this suppression is mediated by the induction of regulatory T cells (Tregs) and dysfunction of circulating tumor specific effector CD8 T cells. To uncover which antigen presenting cell (APC) is responsible for tolerizing T cells in the liver, we have generated a single cell transcriptomic dataset of tumor antigen carrying APCs from different tumor-bearing organs (liver, lung, and breast). This analysis has revealed that, in addition to professional APCs, the liver contains resident APCs, such as liver sinusoidal endothelial cells (LSECs), capable of phagocytosing, processing, and presenting antigens on MHCII and MHCI.

Conclusion: Our data suggests that cancer cells residing in the liver leverage its physiological function and exploit hepatic tolerogenic APCs to suppress anti-tumor immune responses. Using various mouse models, we are dissecting which of these APCs are responsible for inducing Tregs and CD8 T cell dysfunction.