Highlights d cGAS in cancer and STING in host cells are minimal requirements to activate CD8 + T cells d Cancer cells transfer cGAMP to myeloid cells in the TME that make STING-dependent IFN-I d Cancer-cell-intrinsic cGAS improves tumor immunogenicity and response to therapy

The liver is a major metastatic target organ, and little is known about the role of immunity in controlling hepatic metastases. Here, we discovered that the concerted and nonredundant action of two innate lymphocyte subpopulations, conventional natural killer cells (cNKs) and tissue-resident type I innate lymphoid cells (trILC1s), is essential for antimetastatic defense. Using different preclinical models for liver metastasis, we found that trILC1 controls metastatic seeding, whereas cNKs restrain outgrowth. Whereas the killing capacity of trILC1s was not affected by the metastatic microenvironment, the phenotype and function of cNK cells were affected in a cancer type–specific fashion. Thus, individual cancer cell lines orchestrate the emergence of unique cNK subsets, which respond differently to tumor-derived factors. Our findings will contribute to the development of therapies for liver metastasis involving hepatic innate cells.

Myeloid leukocytes are essentially involved in both tumor progression and control. We show that neo-adjuvant treatment of mice with an inhibitor of CSF1 receptor (CSF1R), a drug that is used to deplete tumor-associated macrophages, unexpectedly promoted metastasis. CSF1R blockade indirectly diminished the number of NK cells due to a paucity of myeloid cells that provide the survival factor IL-15 to NK cells. Reduction of the number of NK cells resulted in increased seeding of metastatic tumor cells to the lungs but did not impact on progression of established metastases. Supplementation of mice treated with CSF1R-inhibitor with IL-15 restored numbers of NK cells and diminished metastasis. Our data suggest that CSF1R blockade should be combined with administration of IL-15 to reduce the risk of metastasis.

The liver is a major metastatic target organ, and little is known about the role of immunity in controlling hepatic metastases. Here, we discovered that the concerted and non-redundant action of two innate lymphocyte subpopulations, conventional NK cells (cNKs) and tissue-resident type I Innate Lymphoid Cells (trILC1s), is essential for anti-metastatic defense. Using different preclinical models for liver metastasis, we found that trILC1 control metastatic seeding, whereas cNKs restrain outgrowth. The antimetastatic activity of cNKs is regulated in a tumor type-specific fashion. Thereby, individual cancer cell lines orchestrate the emergence of cNK subsets with unique phenotypic and functional traits. Understanding cancer-cell- as well as innate-cell-intrinsic factors will allow the exploitation of hepatic innate cells for development of novel cancer therapies.

LMTK3 is an oncogenic receptor tyrosine kinase implicated in various types of cancer including breast, lung, gastric and colorectal. We have already demonstrated the contribution of LMTK3 in invasion, migration and transcriptional regulation as well as its involvement in endocrine resistance in breast cancer. Despite the significant progress in understanding the role of LMTK3 in human tumourogenesis, the signalling pathways implicated in LMTK3 regulation still remain to be elucidated. Protein phosphorylation play an essential role in regulating intracellular signal transduction pathways involving almost every aspect of cell activity. In silico phosphoproteomic analysis predicted several potential LMTK3 phosphorylation sites targeted by different kinases including Cyclin-dependent kinase 5 (CDK5), a cytoplasmic proline-directed serine/threonine kinase that is commonly overexpressed in many solid tumours. Interestingly, recent work performed by two different groups showed that CDK5 is a regulator of LMTK1 and LMTK2 in neuronal cells, resulting in axonal outgrowth and potentially influencing a number of neurophysiological processes. By performing a variety of molecular/cellular and biochemical experiments we confirmed the ability of CDK5 to phosphorylate LMTK3 in vitro and identified its exact phosphorylation sites. Moreover, we investigated the consequences of CDK5 phosphorylation on various LMTK3 processes, amongst which its stability, sub-cellular localization, its ability to interact with chromatin and others. In addition, the clinical correlation of CDK5 and LMTK3 expression in cell lines and patients’ samples were assessed. In aggregate, we describe a new cellular pathway encompassing CDK5 and LMTK3 that results in breast cancer tumour progression. Our data will be presented. Citation Format: Giulia Lucchiari, Hua Zhang, Joao Nunes, Yichen Xu, Arnhild Grothey, Justin Stebbing, Georgios Giamas. Role of phosphorylation in Lmtk3 activation and its contribution in breast cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 185.