|NKG2A blocking enhances CD8 T cell anti-cancer immunity synergized with vaccines|
|Anti-Cancer immunotherapy, including immune checkpoint inhibitors and cancer vaccines, faces a stigma of treatment resistance, although intriguing results have been documented in both experimental and clinical settings. Increasing the expression of HLA-E, which physiologically present “self” signals derived from HLA class I molecules to control unwanted immune responses, is a strategy used by tumour cells to escape from attacks of immune cells. The counterpart of the HLA-E/peptide complex is the heterodimeric receptor NKG2A/CD94 expressed by NK and CD8 T cells, whose activation induces inhibitory signals. More importantly, increased activities of the interaction between HLA-E and NKG2A have been observed in cancer vaccine administration, suggesting blockade of NKG2A or HLA-E could be therapeutic intervention to improve the efficacy of cancer vaccines.
In a recent report published in Cell (here), Montfoort and colleagues demonstrate the potential of NKG2A blockade in anti-cancer immune therapy. A majority of NK cells and a fraction of CD8 T cells in the tumour microenvironment of patients with head and neck squamous cell carcinoma (HNSCC) expressed NKG2A. T cells that had immune reactivity against HPV antigens harboured upregulated NKG2A. Data from an open-source database Cancer Genome Atlas Network (TCGA) showed NKG2A and HLA-E could be negative predictors of prognosis in cancers. More importantly, NKG2A-negative CD8 T cells demonstrated the phenotypes of central memory, short-lived effector, and terminally differentiated effector T cells, which had an increased capacity to produce IFN-gamma.Furthermore, in a mouse model of HPV16-induced cancer, a long-peptide vaccine induced strong anti-cancer immune responses, where tumour infiltrating CD8 T cells expressed higher levels of NKG2A after vaccination. However, vaccine-induced tumour control was transit in this model. In order to determine whether blocking of immune checkpoint inhibitors could improve tumour control, anti-PD-1 antibodies were administered to tumour-bearing mice. However, PD-1 blockade did not improve tumour control, whereas NKG2A blocking showed benefit in tumour killing when coordinated with cancer vaccines. The similar anti-tumour effects of NKG2A were also observed in other mouse cancer models administered with corresponding vaccines.
Authors also implanted Qa-1b (the ortholog of HLA-E in mice, which was increased by vaccine treatment)-positive tumours in Qa-1b-deficent mice and treated with NKG2A blockade, where similar anti-tumour effects were also present indicating Qa-1b expression in the stromal cells was dispensable for NKG2A blockade therapy. Upregulation of Qa-1b in tumour cells was induced by IFN-gamma. Moreover, tumour cells lacking Qa-1b expression were showed to be more sensitive to vaccine therapy with enhanced tumour control.
This study highlights the importance of the HLA-E/NKG2A axis in cancer immunotherapy when intratumour inflammation is initiated by vaccines.