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.
Author Info: (1) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (2) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (3)
Author Info: (1) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (2) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (3) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (4) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (5) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (6) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (7) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (8) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. thomas.duhen@providence.org.
