Adaptive subsets limit the anti-tumoral NK-cell activity in Hepatocellular Carcinoma

• Published in: bioRxiv
• Main Authors: Rennert, Charlotte, Tauber, Catrin, Fehrenbach, Pia, Heim, Kathrin, Bettinger, Dominik, Sogukpinar, Oezlem, Schuch, Anita, Britta Franziska Zecher, Bengsch, Bertram, Lang, Sven, Bronsert, Peter, Bjoerkstroem, Niklas K, Fichtner-Feigl, Stefan, Schultheiss, Michael, Thimme, Robert, Hofmann, Maike
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 16.04.2021
• Subjects: Cirrhosis; Cytomegalovirus; Cytometry; Etiology; Hepatitis B; Hepatocellular carcinoma; Liver cancer; Liver cirrhosis; Lymphocytes; Natural killer cells; Phenotypes; Public health
• DOI: 10.1101/2021.04.16.440140

Background and Aims: Hepatocellular carcinoma (HCC) is a global health burden with increasing incidence, poor prognosis and limited therapeutic options. Natural killer (NK) cells exhibit potent anti-tumoral activity and therefore represent potential targets for immunotherapeutic approaches in HCC treatment. However, the human NK-cell repertoire is highly diverse including conventional and adaptive NK cells that differ in phenotype and effector function. Adaptive NK-cell frequencies are increased in association with HCMV (human cytomegalovirus) seropositivity that is also common in HCC patients. In this study, we aimed to gain a better understanding of the NK-cell repertoire and the associated anti-tumoral activity in HCC patients. Methods: In-depth phenotypic and functional flow-cytometry analyses of the HCMV-associated NK cell-repertoire obtained from 57 HCC patients, 33 liver cirrhosis patients and 36 healthy donors (HD). Results: First, adaptive subsets are present in all three cohorts with conserved characteristics in patients with liver cirrhosis and HCC. Second, adaptive NK cells can be isolated from HCC tissue however lack features of tissue-residency and thus probably represent circulating/infiltrating lymphocytes. Third, the anti-tumoral activity by adaptive NK cells is reduced compared to conventional NK-cell subsets, also in HCC. Lastly, frequencies of adaptive NK cells were increased in patients suffering from Hepatitis B virus-associated HCC providing a link between etiology and the NK-cell repertoire in HCC. Conclusion: Adaptive NK cells limit the anti-tumoral activitity of NK cells in HCC, especially in association with HBV infection that is accompanied by an expansion of this NK cell subset. Competing Interest Statement The authors have declared no competing interest.