NKG2A is a late immune checkpoint on CD8 T cells and marks repeated stimulation and cell division. Issue 4 (10th November 2021)

• Record Type: Journal Article
• Authors: Borst, Linda; Sluijter, Marjolein; Sturm, Gregor; Charoentong, Pornpimol; Santegoets, Saskia J.; van Gulijk, Mandy; van Elsas, Marit J.; Groeneveldt, Christianne; van Montfoort, Nadine; Finotello, Francesca; Trajanoski, Zlatko; Kiełbasa, Szymon M.; van der Burg, Sjoerd H.; van Hall, Thorbald
• Is Part Of: International journal of cancer. Volume 150:Issue 4(2022)
• Page Start: 688
• Page End: 704
• Publication Date: 2021-11-10
• Subjects: CD8 T cells -- immune checkpoint -- NKG2A -- TGF‐β -- tumor immunity; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.33859
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: The surface inhibitory receptor NKG2A forms heterodimers with the invariant CD94 chain and is expressed on a subset of activated CD8 T cells. As antibodies to block NKG2A are currently tested in several efficacy trials for different tumor indications, it is important to characterize the NKG2A + CD8 T cell population in the context of other inhibitory receptors. Here we used a well‐controlled culture system to study the kinetics of inhibitory receptor expression. Naïve mouse CD8 T cells were synchronously and repeatedly activated by artificial antigen presenting cells in the presence of the homeostatic cytokine IL‐7. The results revealed NKG2A as a late inhibitory receptor, expressed after repeated cognate antigen stimulations. In contrast, the expression of PD‐1, TIGIT and LAG‐3 was rapidly induced, hours after first contact and subsequently down regulated during each resting phase. This late, but stable expression kinetics of NKG2A was most similar to that of TIM‐3 and CD39. Importantly, single‐cell transcriptomics of human tumor‐infiltrating lymphocytes (TILs) showed indeed that these receptors were often coexpressed by the same CD8 T cell cluster. Furthermore, NKG2A expression was associated with cell division and was promoted by TGF‐β in vitro, although TGF‐β signaling was not necessary in a mouse tumor model in vivo. In summary, our data show that PD‐1 reflects recent TCR triggering, but that NKG2A is induced after repeated antigen stimulations and represents a late inhibitory receptor. Together with TIM‐3 and CD39, NKG2A might thus mark actively dividing tumor‐specific TILs. Abstract : What's new? The immune inhibitory receptor NKG2A is of emerging interest in cancer immunotherapy, with antibodies that target and interrupt NKG2A, in combination with PD‐L1 blockade, yielding promising antitumor responses in ongoing clinical trials. NKG2A expression on CD8 T cells, however, has not been fully charted and thus little is known about its regulation. Here, in vitro analyses of the kinetics of inhibitory receptor expression identify NKG2A as a late immune checkpoint. Its expression, induced upon repeated antigen encounter, is frequently associated with TIM3 and CD39. The findings suggest that NKG2A is a potential marker for the identification of tumor‐specific T cells.