Prdm1 Positively Regulates Liver Type 1 ILCs Cancer Immune Surveillance and Preserves Functional Heterogeneity

Abstract

Liver Type 1 innate lymphoid cells (ILCs) comprise conventional natural killer (cNK) cells and ILC1s. The main functions of Type 1 ILCs not only include directly killing target cells but also regulating the local immune microenvironment of the liver through the secretion of cytokines. Uncovering the intricate mechanisms by which transcriptional factors regulate and influence the functions of Type 1 ILCs, particularly within the context of liver tumors, presents a significant opportunity to amplify the effectiveness of immunotherapies against liver malignancies. Using Ncr1-drived conditional knockout mouse model, our study reveals the regulatory role of Prdm1 in shaping the composition and maturation of liver Type 1 ILCs. Notably, Prdm1 regulates the ratio between NK cells and ILC1s, promoting a shift in the balance towards the direction of NK cells. Although Prdm1 did not affect the killing function of cNK cells in an in vivo cytotoxicity model, a significant increase in cancer metastasis was observed in Prdm1 knockout mice. IFN-γ, granzyme B, and perforin secretion decreased significantly in Prdm1 deficient Type 1 ILCs. scRNA sequencing data also provided evidence that Prdm1 sustains functional subsets of liver type 1 ILCs and facilitates communications between Type 1 ILCs and macrophages. The present study unveiled a novel regulatory mechanism of Prdm1 in liver Type 1 ILCs, showing promising potential for developing innovative immune therapy strategies against liver cancer.