A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

The molecular pathogenesis of chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) is poorly understood. Following the screening of 57 CLPD-NK patients, only five presented STAT3 mutations. WES profiling of 13 cases negative for STAT3/STAT5B mutations uncovered an average of 18 clonal, population rare and deleterious somatic variants per patient. The mutational landscape of CLPD-NK showed that most patients carry a heavy mutational burden, with major and subclonal deleterious mutations co-existing in the leukemic clone. Somatic mutations hit genes wired to cancer proliferation, survival, and migration pathways, in the first place Ras/MAPK, PI3K-AKT, in addition to JAK/STAT (PIK3R1 and PTK2). We confirmed variants with putative driver role of MAP10, MPZL1, RPS6KA1, SETD1B, TAOK2, TMEM127, and TNFRSF1A genes, and of genes linked to viral infections (DDX3X and RSF1) and DNA repair (PAXIP1). A truncating mutation of the epigenetic regulator TET2 and a variant likely abrogating PIK3R1-negative regulatory activity were validated. This study significantly furthered the view of the genes and pathways involved in CLPD-NK, indicated similarities with aggressive diseases of NK cells and detected mutated genes targetable by approved drugs, being a step forward to personalized precision medicine for CLPD-NK patients.Peer reviewe

CD300e shapes the function of tumor-associated macrophages in colorectal cancer

CD300e is a poorly studied immune receptor belonging to the CD300 family of receptors, and initially described as an immune activating molecule whose expression is restricted to myeloid cell lineages. Based on the recent findings that highlighted a potential immune-regulatory function of the receptor in monocytes and macrophages, the present study explored the role of CD300e in modulating the function of tumor-associated macrophages (TAMs) in the context of colorectal cancer (CRC). Among immune cells composing the tumor microenvironment, TAMs are the most abundant population and play a crucial role in supporting tumor growth and progression. An involvement of CD300e was observed at the level of human CRC tissue, and human macrophages exposed to CRC epithelium were shown to upregulate CD300e expression. Importantly, the generation of a CD300e knock out (KO) mouse line allowed to uncover a novel role of CD300e in shaping the functional profile of tumor-associated macrophages in vitro, as well as in promoting tumor development in an in vivo model of CRC. In particular, CD300e KO macrophages were shown to adopt a more pronounced proinflammatory/anti-tumor profile when co-cultured murine tumor colon organoids (TCO), with a reduced ability to induce epithelial to mesenchymal transition and proliferation in TCO. Notably, CD300e KO mice developed a lower tumor burden upon induction of colitis-associated CRC and were protected from colitis detrimental effects; preliminary results indicate that the absence of CD300e also shapes the composition of the gut microbiota in CRC-bearing mice, with an enrichment in protective bacterial taxa in CD300e KO mice. Overall, the results obtained in the present study uncovered a novel function of CD300e as a potential immune checkpoint molecule in CRC and open the way for a deep investigation of CD300e mechanism of action in the tumor context, with the perspective of targeting CD300e as a therapeutic strategy

Tumor Cells and the Extracellular Matrix Dictate the Pro-Tumoral Profile of Macrophages in CRC

none15noopenSara Coletta, Silvia Lonardi, Francesca Sensi, Edoardo D’Angelo, Matteo Fassan, Salvatore Pucciarelli, Arianna Valzelli, Andrea Biccari, William Vermi, Chiara Della Bella, Annica Barizza, Mario Milco D’Elios, Marina de Bernard, Marco Agostini, Gaia CodoloColetta, Sara; Lonardi, Silvia; Sensi, Francesca; D’Angelo, Edoardo; Fassan, Matteo; Pucciarelli, Salvatore; Valzelli, Arianna; Biccari, Andrea; Vermi, William; Della Bella, Chiara; Barizza, Annica; Milco D’Elios, Mario; DE BERNARD, Marina; Agostini, Marco; Codolo, Gai