Fesneau et al. showed that in HNSCC and CRC tumors, expression of the inhibitor NKG2A, a receptor for HLA-E that is associated with poor prognosis for many solid cancers, was upregulated upon differentiation of CD8+ T cells into cytotoxic tumor-reactive CD39+CD103+ double positive (DP) cells. The NKG2A–DP and NKG2A+DP CD8+ T cell TCR repertoires overlapped, suggesting both shared origins and antitumor specificities. NKG2A upregulation on naive CD8+ T cells depended on IL-12 (paradoxically, a promoter of cytotoxic immune responses), TCR and TGFβ stimulation, CD4+ T cells, MHC-II+ cells, and CD40L/CD40 interactions.
Contributed by Paula Hochman
ABSTRACT: Blockade of NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response. Yet the role of NKG2A(+) CD8 T cells in the anti-tumor response and the regulation of NKG2A expression on human tumor-infiltrating T cells are still poorly understood. Here, by performing CITE-seq on T cells derived from head and neck squamous cell carcinoma and colorectal cancer, we show that NKG2A expression is induced on CD8 T cells differentiating into cytotoxic, CD39(+)CD103(+) double positive (DP) cells, a phenotype associated with tumor-reactive T cells. This developmental trajectory leads to TCR repertoire overlap between the NKG2A(-) and NKG2A(+) DP CD8 T cells, suggesting shared antigen specificities. Mechanistically, IL-12 is essential for the expression of NKG2A on CD8 T cells in a CD40/CD40L- dependent manner, in conjunction with TCR stimulation. Our study thus reveals that NKG2A is induced by IL-12 on human tumor-reactive CD8 T cells exposed to a TGF-_-rich environment, highlighting an underappreciated immuno-regulatory feedback loop dependent on IL-12 stimulation.
