Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells

Kamiya, Takahiro; Seow, See Voon; Wong, Desmond; Robinson, Murray O.; Campana, Dario

doi:10.1172/jci123955

Cited by 270 publications

(220 citation statements)

References 87 publications

(127 reference statements)

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“…NKG2A is one of the inhibitory receptors in the KIRs family, which is well-demonstrated to play a crucial role in chronic infection. As NKG2A was originally identified on NK cells, most studies about NKG2A + cells were focused on NK cells both in chronic infection and in cancer (4,6,15). However, the exact subsets of NKG2A + cells in human lung cancer tissue were unclear.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study showed that NKG2A promoted NK cell exhaustion and facilitated chronic hepatitis C virus infection in a mouse model (12). Recently, emerging evidence has demonstrated that the NKG2A blockade could promote both the NK and CD8 + T cell-mediated anti-tumor effect (13)(14)(15). Despite the remarkable progress in the understanding of the NKG2A blockade in tumor immunotherapy, there are many gaps in knowledge.…”

Section: Introductionmentioning

confidence: 99%

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CD8+ T Cells Form the Predominant Subset of NKG2A+ Cells in Human Lung Cancer

et al. 2020

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Background: NKG2A is an inhibitory receptor of both T cells and natural killer (NK) cells. Persistent activation promotes T cells and NK cells to express NKG2A and results in the progression of chronic infection and cancer. However, the characteristics and subsets of NKG2A + lymphocytes in human lung cancer are still unclear.Methods: Here, we used the Tumor Immune Estimation Resource database and immune profiling of paired biospecimens to uncover the correlation between NKG2A expression and immune infiltration levels in human cancer as well as the characteristics of NKG2A + lymphocytes in human lung cancer.Results: We found that KLRC1 expression was especially correlated with CD8 + T-cell infiltration levels in 34 types of human cancer through the Tumor Immune Estimation Resource database. Moreover, NKG2A + CD8 + T cells were the predominant subset of NKG2A + lymphocytes in human lung cancer. In contrast, the NKG2A + NK cells were decreased in tumors compared with the paired normal lung tissue. Tumor-infiltrating NKG2A + CD8 + T cells expressed tissue-resident memory T cell (T RM cell) and exhausted T-cell markers. Cytokines and cytotoxic molecules secreted by tumor-infiltrating NKG2A + CD8 + T cells were significantly lower than those secreted by NKG2A − CD8 + T cells in vitro. When stimulated with T-cell receptor activator, tumor-infiltrating NKG2A + CD8 + T cells could secrete large amounts of granzyme B.Conclusions: Our findings demonstrate that tumor-infiltrating NKG2A + CD8 + T cells form the predominant subset of NKG2A + cells in human lung cancer and suggest that targeting NKG2A + CD8 + T cells is a promising approach for future anti-lung cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD8+ T Cells Form the Predominant Subset of NKG2A+ Cells in Human Lung Cancer

et al. 2020

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“…A recent preclinical study used protein expression blockers (PEBLs), engineered protein constructs consisting of an scFv against a target protein that is linked to an ER/Golgi retention peptide to prevent the transport of NKG2A to the cell surface. In this study, PEBLs enhanced NK cell cytotoxicity and antitumor functions (126). Interestingly, preventing NKG2A expression via PEBLs enhanced NK cell in vitro cytotoxicity more than NKG2A antibody blockade.…”

Section: Cytokine Therapy: Mobilizing Nk Cells In Cancermentioning

confidence: 52%

Killers 2.0: NK cell therapies at the forefront of cancer control

Hodgins

Khan

Park

et al. 2019

Journal of Clinical Investigation

169

127

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The existence of immune cells that mediate cellular cytotoxicity without prior activation was determined by multiple groups who reported the spontaneous killing of tumor cells by lymphocytes from unimmunized mice (1-3). We now know that these cells with natural cytotoxicity, or natural killer (NK) cells, are important mediators of cancer immunosurveillance. NK cells are a heterogeneous population, and in humans they have been historically divided into IFN-γ-producing CD56 hi CD16 + and cytotoxic CD56 lo CD16 hi (4), whereas in mice they are grouped according to their expression of CD27 and CD11b (5), although it is now clear that the complexity is much higher. Distinct NK cell subsets play different roles in tumor immunity and cancer immunotherapy, as reviewed in Stabile et al. (6). NK cells are equipped with many receptors that tightly regulate their activation and allow them to discriminate between "normal" and "dangerous" cells (7). In addition to regulating NK cell activation, signals coming from activating and inhibitory receptors also tune the steady-state responsiveness of NK cells to future stimuli, in a process called NK cell education (reviewed in refs. 8, 9). Inhibitory receptors, such as killer-cell immunoglobulinlike receptors (KIRs), deliver negative signals that prevent NK cell autoreactivity. KIRs and other inhibitory receptors recognize MHC I molecules, whose absence may result in NK activation, the so-called "missing-self recognition" (10, 11). Later studies showed that lack of MHC expression was not sufficient or necessary to induce NK activation; rather, signaling from activating receptors was required. Broadly speaking, activating receptors, including NKG2D, provide activating signals upon binding to stress-induced ligands on target cells, which is referred to as "induced-self recognition" (12, 13). Ultimately, NK activation depends on the balance between activating and inhibitory signals triggered by these receptors binding their ligands. When activating signals prevail, NK cells respond, whereas when inhibitory signaling is stronger, NK cells do not respond. Healthy cells, with some exceptions (14-16), express low levels of activating ligands and an abundance of inhibitory ligands and therefore are not attacked by NK cells. On the other hand, tumor cells often acquire expression of NK cellactivating ligands and/or lose expression of MHC molecules. NK cells sense and respond to changes in the repertoire of molecules expressed on the surface of healthy cells during cellular transformation. This positions NK cells as important sentinels against cancer and as prime targets for cancer immunotherapy (17).

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“…However, p53-expressing senescent liver tumor cells recruit NK cells by inducing the chemokine CCL2 but not CCL3, CCL4 or CCL5, in senescent tumor cells without affecting the ligand expression of RAE-1 proteins in the tumor cells [153]. Collectively, agents blocking the interaction between HLA-E and NKG2A [124], the humanized anti-NKG2A monoclonal antibody monalizumab [154] and NKG2A protein expression blockers [155] would be promising strategies for the immune clearance of senescent cells and subsequent anti-ageing and chronic diseases. Additionally, chimeric antigen receptor (CAR)-NK cells may be a valuable tool for senescence immune surveillance.…”

Section: Roles and Regulation Of Nk Cells In Senescent Cell Removalmentioning

confidence: 99%

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

Song

2020

Cells

135

115

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Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing. Immune cells can remove senescent cells. Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells. Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases. This short review provides an overview of the research progress to date concerning senescent cell-caused chronic diseases and tissue ageing, as well as the regulation of senescence by small-molecule drugs in clinical trials and different roles and regulation of immune cells in the elimination of senescent cells. Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.

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Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells

Cited by 270 publications

References 87 publications

CD8+ T Cells Form the Predominant Subset of NKG2A+ Cells in Human Lung Cancer

CD8+ T Cells Form the Predominant Subset of NKG2A+ Cells in Human Lung Cancer

Killers 2.0: NK cell therapies at the forefront of cancer control

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

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