Phd in IINNOVATION IN IMMUNO-MEDIATED AND HEMATOLOGICAL DISORDERS

Thesis title: NK cell plasticity is promoted by CXCR3-mediated interplay with macrophages in a murine model of colorectal cancer liver metastases

The liver is the major metastatic target organ for colorectal cancer (CRC), but little is known about the related innate lymphoid immune contexture. Indeed, healthy livers are disseminated by a large population of innate lymphocytes, but their behavior in the metastatic niche is not fully understood. This study aims to comprehend the mechanisms governing the function of group 1 innate lymphoid cells (ILCs) in metastasis engraftment and progression by investigating their phenotypic plasticity and behavior within the metastatic niche. By taking advantage of a CRC mouse model of liver metastasis, we show that NK cell/ILC1 are involved in controlling hepatic metastasis formation. We report poor infiltration of ILC1 and expansion of a CD49a+ CD49b+ population (ILC1-like cells) among tumor-infiltrating lymphocytes. Through RNA-seq of sorted ILC1s, NK cells, and ILC1-like cells, along with multiparametric flow cytometry, we unraveled induction of specific metastasis-induced phenotypes associated to immune suppression and migration. Furthermore, macrophages increase both in metastatic nodules and metastasis-free tissue and promote generation of ILC1-like cells through TGF-β expression in vitro. In addition, in vivo depletion of metastasis-associated macrophages (MAMs) corresponds to reduced generation of ILC1-like cells. Ultimately, a comparison of metastasis in CXCR3+/+ or CXCR3-/- mice showed that CXCR3 deficiency inhibits ILC1-like cell accumulation and corresponds to reduced infiltration of monocytes and macrophages. In summary, our study demonstrates that NK cells infiltrate metastases and convert into ILC1-like cells under the effect of TGF-β produced by MAMs. Reduced accumulation of MAMs in CXCR3-/- mice results in abrogation of NK cell differentiation into ILC1-like cells. Indeed, CXCR3 may drive the interplay between NK cells and macrophages in this context. Overall, this work defines mechanisms of NK/ILC distribution and function in metastatic lesions offering insights that may lead to new strategies for metastasis prevention and therapy.