Targeting natural killer cells in solid tumors

Natural killer(NK)cells are innate lymphoid cells endowed with cytolytic activity and a capacity to secrete cytokines and chemokines.Several lines of evidence suggest that NK cells play an important role in anti-tumor immunity.Some therapies against hematological malignacies make use of the immune properties of NK cells,such as their ability to kill residual leukemic blasts efficiently after conditioning during haploidentical hematopoietic stem cell transplantation.However,knowledge on NK cell infiltration and the status of NK cell responsiveness in solid tumors is limited so far.The pro-angiogenic role of the recently described NK cell-like type 1 innate lymphoid cells(ILC1s)and their phenotypic resemblance to NK cells are confounding factors that add a level of complexity,at least in mice.Here,we review the current knowledge on the presence and function of NK cells in solid tumors as well as the immunotherapeutic approaches designed to harness NK cell functions in these conditions,including those that aim to reinforce conventional anti-tumor therapies to increase the chances of successful treatment.

Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia

Natural killer(NK)cells are innate cytotoxic lymphoid cells(ILCs)involved in the killing of infected and tumor cells.Among human and mouse NK cells from the spleen and blood,we previously identified by single-cell RNA sequencing(scRNAseq)two similar major subsets,NK1 and NK2.Using the same technology,we report here the identification,by single-cell RNA sequencing(scRNAseq),of three NK cell subpopulations in human bone marrow.Pseudotime analysis identified a subset of resident CD56^(bright) NK cells,NK0 cells,as the precursor of both circulating CD56dim NK1-like NK cells and CD56^(bright) NK2-like NK cells in human bone marrow and spleen under physiological conditions.Transcriptomic profiles of bone marrow NK cells from patients with acute myeloid leukemia(AML)exhibited stress-induced repression of NK cell effector functions,highlighting the profound impact of this disease on NK cell heterogeneity.Bone marrow NK cells from AML patients exhibited reduced levels of CD160,but the CD160high group had a significantly higher survival rate.

Correction:Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia

Correction to:Cellular&Molecular Immunology https://doi.org/10.1038/S41423-020-00574-8,published online 25 November 2020 In the version of this article initially published,two unintended errors were made during manuscript preparation.(1)The figure legend for Panel 3B was missing;the correct legend is as follows.

Germinal center-dependent and-independent immune responses of tumor-infiltrating B cells in human cancers

B cells play essential roles in immunity,mainly through the production of high affinity plasma cells(PCs)and memory B(Bmem)cells.The affinity maturation and differentiation of B cells rely on the integration of B-cell receptor(BCR)intrinsic and extrinsic signals provided by antigen binding and the microenvironment,respectively.In recent years,tumor infiltrating B(TIL-B)cells and PCs(TIL-PCs)have been revealed as important players in antitumor responses in human cancers,but their interplay and dynamics remain largely unknown.In lymphoid organs,B-cell responses involve both germinal center(GC)-dependent and GC-independent pathways for Bmem cell and PC production.Affinity maturation of BCR repertoires occurs in GC reactions with specific spatiotemporal dynamics of signal integration by B cells.In general,the reactivation of high-affinity Bmem cells by antigens triggers GC-independent production of large numbers of PC without BCR rediversification.Understanding B-cell dynamics in immune responses requires the integration of multiple tools and readouts such as single-cell phenotyping and RNA-seq,in situ analyses,BCR repertoire analysis,BCR specificity and affinity assays,and functional tests.Here,we review how those tools have recently been applied to study TIL-B cells and TIL-PC in different types of solid tumors.We assessed the published evidence for different models of TIL-B-cell dynamics involving GC-dependent or GC-independent local responses and the resulting production of antigen-specific PCs.Altogether,we highlight the need for more integrative B-cell immunology studies to rationally investigate TIL-B cells as a leverage for antitumor therapies.

Reply to ‘Comment to: Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia’

We thank Melsen et al.for their interest in our study.Their remarks allow us to clarify key aspects of our work on human bone marrow NK cell biology.1 Our study reports the unsupervised single-cell analysis of NK cells from eight healthy donors and eight acute myeloid leukemia(AML)patients.1 First,we detected an adaptive NK cell subset that correlated with the cytomegalovirus(CMV)positivity status of the donors.