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• DMTs induced diverse effects on immune cells with no common signature observed. • Fingolimod, alemtuzumab and DMF reduced T cell numbers, being fingolimod more acute. • Teriflunomide or IFNβ had no effect on T cell subsets; natalizumab had modest impact. • DMTs affected B, NK, and NKT cells in diverse ways, lacking clear patterns. • Time since last infusion of alemtuzumab or natalizumab affected T or NK cell subsets. Disease modifying therapies (DMTs) used for treating people with relapsing-remitting multiple sclerosis (pwRRMS) target the immune system by different mechanisms of action. However, there is a lack of a comprehensive assessment of their effects on the immune system in comparison to treatment-naïve pwRRMS. Herein, we evaluated the numbers of circulating B cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs), natural killer (NK) cells and NKT cells, and their subsets, in pwRRMS who were treatment-naïve or treated with different DMTs. Compared to treatment-naïve pwRRMS, common and divergent effects on immune system cells were observed on pwRRMS treated with different DMTs, with no consistent pattern across all therapies in any of the cell populations analysed. PwRRMS treated with fingolimod, dimethyl fumarate (DMF), or alemtuzumab have reduced numbers of CD4+ and CD8+ T cells, as well as Treg subsets, with fingolimod causing the most pronounced decrease in T cell subsets. In contrast, teriflunomide and interferon (IFN) β have minimal impact on T cells, and natalizumab marginally increases the number of memory T cells in the blood. The effect of DMTs on the B cell, NKT and NK cell subsets is highly variable with alemtuzumab inducing a strong increase in the number of the most immature NK cells and its subsets. This study comprehensively evaluates the magnitude of the effect of different DMTs on blood immune cells providing a better understanding of therapy outcome. Furthermore, the lack of a discernible pattern in the effects of DMTs on blood immune cells suggests that multiple immune cells can independently modulate the disease. [ABSTRACT FROM AUTHOR]

The enhancement of T cell and NK cell function is an immunotherapeutic strategy for combating cancer. Antibodies that block inhibitory receptors, such as PD-1 and CTLA4, augment T cell function and have been successful in curing patients with some types of cancer. As an alternative approach to targeting specific inhibitory receptors by antibodies, small molecule drugs that inhibit negative regulators of T cell activation have been sought. One potential pharmacological target is diacylglycerol (DAG) kinase (DGK)ζ, which is an enzyme that acts as a negative regulator of DAG by phosphorylating DAG and converting it into phosphatidic acid. DAG-mediated signaling is critical for T cell activation through its T cell receptor and NK cell activation downstream of a variety of activating receptors. Thus, DGKζ-deficient T cells and NK cells display increased function upon activating receptor engagement. Moreover, treatment with the DGKζ-selective inhibitor ASP1570 augments T cell function. In this study, we sought to test whether the acute inhibition of DGKζ by ASP1570 augments NK cell function. We find that ASP1570 enhances DAG-mediated signaling in immunoreceptor-stimulated NK cells. Accordingly, ASP1570 treatment enhanced IFNγ production and degranulation of immunoreceptor-activated NK cells in vitro and NK cell-mediated tumor clearance in vivo. Thus, ASP1570 enhances both T and NK cell function, which could possibly induce more durable anti-tumor responses for immunotherapy. [ABSTRACT FROM AUTHOR]

• Single-cell transcriptome data revealed the heterogeneity of NK cells in NSCLC. • Proportion of infiltrating immature NK cells was higher in responsive NSCLC patients receiving anti-PD-1 therapy. • Immature NK cells showed strong interactions with Th1 cells, Th17 cells and effector CD8+ T cells. • CXCR4 was a significant marker gene of immature NK cells and linked to activation of Th17 cells and infiltration of CD8+ T cells. The efficacy of immune checkpoint inhibitors remains limited in non-small cell lung cancer (NSCLC). Natural killer (NK) cells serve as the key element of innate immunity and play an important role in anti-tumor immunity, the impact of NK cells on efficacy of anti-PD-1 therapy in NSCLC is worth exploring. We analyzed single-cell transcriptome data derived from biopsies of NSCLC patients receiving anti-PD-1 treatment. Immune cell subtypes were identified and further cell–cell communication were analyzed and verified. We observed totally 6 distinct NK cells clusters in NSCLC infiltrating immune cells. It's worth noting that enrichment of immature NK cells was found in responsive group. A series of marker genes of immature NK cells were associated with anti-PD-1 response and related to immune regulation processes such as antigen processing, Th1, Th17 cells activation. Moreover, effector CD8+ T cells were significantly enriched in responsive group and showed similar trajectories with immature NK cells. Cell-cell communication analysis showed that immature NK cells showed strong interactions with Th17 cells and effector CD8+ T cells. Furthermore, when validating the expression of immature NK cells marker genes, we found that CXCR4 was associated with enriched infiltration of CD8+ T cells. In conclusion, immature NK cells may facilitate the efficacy of anti-PD-1 therapy by interacting with Th1 cells, Th17 cells and enhancing infiltration of effector CD8+ T cells. Our data suggested that NK cells could be a promising target to improve the prognosis of NSCLC patients. [ABSTRACT FROM AUTHOR]

• This study is the first one to show that the changes of peripheral lymphocyte subsets are associated with the survival of prostate cancer(PCa) patients. • The lower absolute counts of peripheral lymphocyte subsets are unfavorable factors for the survival of patients with PCa. • Peripheral lymphocyte subsets will assist clinicians to evaluate the degree of immune impairment in patients with PCa, and assess their survival status. Many studies have sought associations between the total peripheral blood lymphocyte count and prostate cancer (PCa) prognosis, but not peripheral lymphocyte subsets. We explored the associations between the absolute counts of peripheral lymphocyte subsets and PCa patient survival. 135 PCa patients were included in this study. The log-rank test and Kaplan-Meier method were employed to compare overall survival (OS) and progression-free survival (PFS) rates. Univariate and multivariate Cox's regression analyses were employed to identify prognostic factors. Flow cytometry analysis was used to determine the numbers of peripheral lymphocyte subsets. PCa patients with lower absolute counts of certain lymphocyte subsets showed poorer PFS and OS than those with higher absolute counts of these cells. The numbers of CD4+ T cells, CD3+ T cells, and natural killer (NK) cells were significantly higher in PCa patients of tumor node metastasis (TNM) Ⅰ-Ⅱ stages than those of TNM ⅠIII-IV stages. Univariate and multivariate Cox's regression analyses of OS and PFS indicated that neutrophil numbers > 4.81*109/L, CD4+ T cells ≤ 254 /μL, and NK cells ≤ 136 /μL were unfavorably prognostic for patients with PCa. Lower absolute counts of certain peripheral lymphocyte subsets (NK cells ≤ 136/μL and CD4+ T cells ≤ 254/μL) are prognostically unfavorable for PCa patients. [ABSTRACT FROM AUTHOR]