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Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non–small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. Experimental Design: We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis). Results: We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12–0.51; P < 0.0001). Conclusions: As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

The success of immunotherapy has highlighted the critical role of the immune microenvironment in acute lymphoblastic leukemia (ALL); however, the immune landscape in ALL remains incompletely understood and most studies have focused on conventional T cells or NK cells. This study investigated the prognostic impact of circulating γδ T-cell alterations using high-dimensional analysis in a cohort of newly diagnosed adult ALL patients (10 B-ALL; 9 Philadelphia+ ALL; 9 T-ALL). Our analysis revealed common alterations in CD8+ T cells and γδ T cells of relapsed patients, including accumulation of early stage differentiation and increased expression of BTLA and CD73. We demonstrated that the circulating γδ T-cell signature was the most discriminating between relapsed and disease-free groups. In addition, Vδ2 T-cell alterations strongly discriminated patients by relapse status. Taken together, these data highlight the role of ɣδ T cells in adult ALL patients, among whom Vδ2 T cells may be a pivotal contributor to T-cell immunity in ALL. Our findings provide a strong rationale for further monitoring and potentiating Vδ2 T cells in ALL, including in the autologous setting.

Purpose:Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non–small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. Experimental Design:We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis).Results:We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12–0.51; P < 0.0001).Conclusions:As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Supplementary Figure 1: Graphical Abstract Supplementary Figure 2: Overall Survival in NSCLC patients treated with pembrolizumab in KEYNOTE-001 according to EGFR mutation Supplementary Figure 3: Recursive partitioning identified classical monocytes and NK as the main immune populations whose frequency splits patients into distinct patterns of overall survival Supplementary Figure 4: Classical monocytes, NK cells and ICOS+ CD4+ T cells are associated with improved pembrolizumab efficacy in advanced NSCLC patients. Supplementary Figure 5: Gating strategy of the 3 main immune populations associated with pembrolizumab efficacy. Supplementary Figure 6: Comparison side by side of Maxstat cut-offs with cut-off from Younden index for overall survival in the 3 populations of interest. Supplementary Figure 7: Survival outcomes in NSCLC patients treated with pembrolizumab in KEYNOTE-001 according to blood baseline frequency of classical monocytes. Supplementary Figure 8: Baseline immune peripheral score is also associated with PFS in melanoma patients treated with PD-1 inhibitors.

Significance This work provides a report of accumulation of unconventional CD56−CD16+ NK cells in nonvirally induced malignancies. Increased frequency of CD56−CD16+ NK cells is associated with adverse clinical outcome in AML, as well as other maturation defects, and might contribute to a defective control of AML progression. Pseudotime analysis highlights a disruption in the maturation process of conventional NK cells in AML patients, leading to a bifurcation point absent in healthy subjects. This analysis, combined with the reduced frequency of conventional NK cells observed in AML patients, suggests that unconventional CD56−CD16+ NK cells derive from an aberrant maturation of conventional NK cells. Overall, accumulation of CD56−CD16+ NK cells could be an important feature of immune escape from innate immunity., Natural killer (NK) cells are major antileukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the current work, we highlight an accumulation of CD56−CD16+ unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly diagnosed AML (n = 48, HEMATOBIO cohort, NCT02320656) and healthy subjects (n = 18) by mass cytometry. We showed evidence of a moderate to drastic accumulation of CD56−CD16+ unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30 and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56−CD16+ NK cells at diagnosis was associated with an adverse clinical outcome and decreased overall survival (HR = 0.13; P = 0.0002) and event-free survival (HR = 0.33; P = 0.018) and retained statistical significance in multivariate analysis. Pseudotime analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56−CD16+ NK cells. Overall, our data suggest that the accumulation of CD56−CD16+ NK cells may be the consequence of immune escape from innate immunity during AML progression.

Natural killer (NK) cells are major anti-leukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the present work, we highlight an accumulation of CD56-CD16+ unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly-diagnosed AML (N=48, HEMATOBIO cohort, NCT02320656) and healthy subjects (N=18) by mass cytometry. We evidenced a moderate to drastic accumulation of CD56- CD16+ unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30, and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56-CD16+ NK cells at diagnosis was associated with an adverse clinical outcome, with decreased overall survival (HR=0.13; P=.0002) and event-free survival (HR=0.33; P=.018), and retained statistical significance in multivariate analysis. Pseudo-time analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56-CD16+ NK cells. Overall, our data suggest that the accumulation of CD56-CD16+ NK cells may be the consequence of immune escape from innate immunity during AML progression.SignificanceThis work provides the first report of accumulation of unconventional CD56-CD16+ NK cells in non-virally induced malignancies. Pseudotime analysis highlights a bifurcation point occurring during the course of NK cell maturation, providing elements regarding the possible origin of CD56-CD16+ NK cells. Increased frequency of CD56-CD16+ NK cells is associated with adverse clinical outcome in AML and might contribute, as well as other maturation defects, to a defective control of AML progression. Overall, accumulation of CD56-CD16+ NK cells could be an important feature of immune escape from innate immunity.Graphical abstractKey pointsA disruption in the maturation process of NK cells leads to accumulation of unconventional CD56- CD16+ NK cells in patients with AMLHigh frequency of CD56-CD16+ NK cells is associated with adverse clinical outcome

NK cells are innate immune cells with inherent capabilities in both recognizing and killing cancer cells. NK cell phenotypes and functional alterations are being described with increasing precision among patients harboring various cancer types, emphasizing the critical role that NK cells play in antitumor immune responses. In addition, advances in understanding NK cell biology have improved our knowledge of such alterations, thereby expanding the potential exploitation of NK cells’ anticancer capabilities. In this review, we present an overview of (1) the various types of NK cell alterations that may contribute to immune evasion in cancer patients and (2) the various strategies to improve NK cell-based anticancer immunotherapies, including pharmacologic modulation and/or genetic modification.

It can be deduced from this concise review that bradykinin and polyphenols could have a double role in health. Nevertheless, if their bioavailability is improved by their encapsulation, polyphenols could diminish the binding affinity of bradykinin to its receptors by causing a conformational rearrangement of the peptide. Besides, the interaction between polyphenols and bradykinin should play a role in pain. Indeed, the formation of the polyphenol-bradykinin aggregates might alleviate the pain sensation caused by bradykinin by preventing: the production of nitric oxide, the activation of phospholipase A2, as well as that of nuclear factor-kappa B. To conclude, this work falls within the basic science, given that it seeks to provide a probable biochemical mechanism of the pharmacological action of polyphenols on the pain sensation caused by bradykinin.

The good nutritional value and the interesting biological activities of the plant-based nutraceuticals are primarily due to the polyphenols. These latter are among the most important and extensively studied plant secondary metabolites and their interaction with proteins is the subject of considerable researches. This interaction is fundamental to the rational design of functional foods as well as to improve the bioavailability and the biofunctionality of the polyphenols. In this work, we emphasized that the types of proteins and polyphenols influence this interaction and chemical bindings are primarily hydrophobic interactions and hydrogen bonds. We highlighted further the anti- atherosclerosis, anti-inflammatory, anti-diabetic, neuro-protective, antioxidant, anti-proliferative, antimicrobial and the hepatoprotective activities of the polyphenols. We also mentioned that astringency and these health benefits may be caused by the interaction with proteins, and that the proteins targeted by polyphenols are: Kelch-like ECH-associated protein 1, extracellular microbial enzymes, phospholipase A2, monoamine oxidase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, laminin receptor, hepatitis C virus NS3 protease, virus-encoded integrase, retroviral reverse transcriptase, leukotoxin, enterotoxin, cholera toxin, α-glucosidase, α-amylase, pro-oxidant enzymes, nuclear factor kappa B, cytochrome P450, metalloproteinases, β- and γ-secretases. A healthy, balanced diet and rich in polyphenols can prevent and even control the major public health problems worldwide.