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Front Immunol. 2019 Aug 21;10:1963. doi: 10.3389/fimmu.2019.01963. eCollection 2019.

Different Features of Tumor-Associated NK Cells in Patients With Low-Grade or High-Grade Peritoneal Carcinomatosis.

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Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Department of Surgical Sciences and Integrated Diagnostics, IRCCS Policlinico San Martino, University General Hospital, University of Genoa, Genoa, Italy.
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
Department of Informatic Bioengineering, Robotic and System Engineering, University of Genoa, Genoa, Italy.
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.
Department of Immunology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
Department of Earth Science, Environment and Life, University of Genoa, Genoa, Italy.


Peritoneal carcinomatosis (PC) is a rare disease defined as diffused implantation of neoplastic cells in the peritoneal cavity. This clinical picture occurs during the evolution of peritoneal tumors, and it is the main cause of morbidity and mortality of patients affected by these pathologies, though cytoreductive surgery with heated intra-peritoneal chemotherapy (CRS/HIPEC) is yielding promising results. In the present study, we evaluated whether the tumor microenvironment of low-grade and high-grade PC could affect the phenotypic and functional features and thus the anti-tumor potential of NK cells. We show that while in the peritoneal fluid (PF) of low-grade PC most CD56dim NK cells show a relatively immature phenotype (NKG2A+KIR-CD57-CD16dim), in the PF of high-grade PC NK cells are, in large majority, mature (CD56dimKIR+CD57+CD16bright). Furthermore, in low-grade PC, PF-NK cells are characterized by a sharp down-regulation of some activating receptors, primarily NKp30 and DNAM-1, while, in high-grade PC, PF-NK cells display a higher expression of the PD-1 inhibitory checkpoint. The compromised phenotype observed in low-grade PC patients corresponds to a functional impairment. On the other hand, in the high-grade PC patients PF-NK cells show much more important defects that only partially reflect the compromised phenotype detected. These data suggest that the PC microenvironment may contribute to tumor escape from immune surveillance by inducing different NK cell impaired features leading to altered anti-tumor activity. Notably, after CRS/HIPEC treatment, the altered NK cell phenotype of a patient with a low-grade disease and favorable prognosis was reverted to a normal one. Our present data offer a clue for the development of new immunotherapeutic strategies capable of restoring the NK-mediated anti-tumor responses in association with the CRS/HIPEC treatment to increase the effectiveness of the current therapy.


NK cell receptors; NKp30; PD-1/PD-L; human NK cells; immune checkpoint; immune escape; peritoneal carcinomatosis; pseudomyxoma peritonei

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