High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer

Abstract

: As the predominant lymphocyte subset in the liver, natural killer (NK) cells have been shown to be highly associated with the outcomes of patients with chronic hepatitis B virus infection (CHB) and hepatocellular carcinoma (HCC). Previously, we reported that NKG2A, a checkpoint candidate, mediates human and murine NK cell dysfunction in CHB. However, NK cell exhaustion and, particularly, the level of NKG2A expression within liver tumors have not been reported. : In this study, we analyzed NKG2A expression and the related dysfunction of NK cells located in intra- or peritumor regions of liver tissue samples from 207 HCC patients, in addition to analyzing disease outcomes.: The expression of NKG2A in NK cells and the NKG2A ligand, HLA-E, in intratumor HCC tissues was observed to be increased. These NK cells, and particularly CD56 NK cells, with higher NKG2A expression showed features of functional exhaustion and were associated with a poor prognosis. The increase in NKG2A expression might be induced by IL-10, which was present at a high level in the plasma of HCC patients. Blocking IL-10 could specifically inhibit NKG2A expression in NK cells. : These findings indicate that NKG2A expression is influenced by factors from cancer nests and contributes to NK cell exhaustion, suggesting that NKG2A blockade has the potential to restore immunity against liver tumors by reversing NK cell exhaustion.

Deficient Natural Killer Cell NKp30‐Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma

“…Functional deficiencies of circulating and intralesional NK cells have been demonstrated in various human cancers, including HCC . Nevertheless, the mechanisms responsible for altered NK cell effector function and their association with disease progression remain largely unexplored.…”

Targeting NKG2A to elucidate natural killer cell ontogenesis and to develop novel immune-therapeutic strategies in cancer therapy

“…The increased expression of NKG2A in tumor‐infiltrating NK cells is also emerging as a contributor in determining the poor prognosis of cancer. In this regard, the NKG2A expression in liver‐resident and tumor‐infiltrating NK cells correlates with NK cell exhaustion and it is associated with a shorter OS of patients affected by hepatocellular carcinoma patients . Moreover, the up‐regulation of NKG2A on NK cells in patients with lung cancer is a predictive factor of tumor metastatization .…”

Genetic reprogramming for NK cell cancer immunotherapy with CRISPR/Cas9

“…10 Furthermore, due to potentially less severe side-effects and fewer costs compared with chimeric antigen receptor (CAR)-T-cells, NK cells have emerged as a safe and effective alternative as CARmodified immune cells for cancer immunotherapy. [13][14][15] In addition, tumour-associated NK cells undergo differentiation to type 1 innate lymphoid cells (ILC1) with decreased anti-tumour effector functions, thus losing control of tumour growth. [13][14][15] In addition, tumour-associated NK cells undergo differentiation to type 1 innate lymphoid cells (ILC1) with decreased anti-tumour effector functions, thus losing control of tumour growth.…”