Human CXCR5+PD-1+ CD8 T cells in healthy individuals and patients with hematologic malignancies

Immune checkpoint blockade (ICB) has revolutionized cancer therapy, but varying response rates illustrate the need for biomarkers of response. Studies in mice have identified a subset of CD8 T cells that is essential for response to PD-1 ICB. These CD8 T cells co-express CXCR5, PD-1 and Tcf1, and provide effector T cells upon PD-1 ICB. It is unknown whether similar T cells play a role in PD-1 ICB in humans. We studied human peripheral blood and lymph nodes (LNs) for the frequency, phenotype, and functionality of CXCR5⁺PD-1⁺ CD8 T cells. We find that CXCR5⁺PD-1⁺ CD8 T cells are memory-like cells, express Tcf1, and lack expression of effector molecules. CXCR5⁺PD-1⁺ CD8 T cells produce cytokines upon stimulation, but have limited proliferative capacity. We studied patients with hematologic malignancies with varying response rates to PD-1 ICB. Specifically in chronic lymphocytic leukemia, in which PD-1 ICB does not induce clinical responses, CXCR5⁺PD-1⁺ CD8 T cells show loss of the memory phenotype and increased effector differentiation. In conclusion, we identified CXCR5⁺PD-1⁺ CD8 T cells in human peripheral blood and LN, which could play a similar role during PD-1 ICB. Future studies should analyze CXCR5⁺PD-1⁺ CD8 T cells during PD-1 ICB and their importance for therapeutic response.     

Combined Env- and Gag-specific T cell responses in relation to programmed death-1 receptor and CD4+ T cell loss rates in human immunodeficiency virus-1 infection

Additional progression markers for human immunodeficiency virus (HIV) infection are warranted. In this study we related antigen-specific responses in CD4⁺ and CD8⁺ T cells to CD38, reflecting chronic immune activation, and to CD4⁺ T cell loss rates. Clones transiently expressing CD107a (CD8⁺) or CD154 (CD4⁺) in response to Gag, Env and Nef overlapping peptide pools were identified, along with their expression of the inhibitory programmed death-1 receptor (PD-1) in fresh peripheral blood mononuclear cells (PBMC) from 31 patients off antiretroviral treatment (ART). HIV-specific CD8⁺ T cell responses dominated over CD4⁺ T cell responses, and among CD8⁺ responses, Gag and Nef responses were higher than Env-responses (P < 0·01). PD-1 on CD8⁺ HIV-specific subsets was higher than CMV-specific CD8⁺ cells (P < 0·01), whereas PD-1 on HIV-specific CD4⁺ cells was similar to PD-1 on CMV-specific CD4⁺ cells. Gag and Env CD8⁺ responses correlated oppositely to the CD4 loss rate. Env/Gag CD8⁺ response ratios, independently of PD-1 levels, correlated more strongly to CD4 change rates (r = −0·50 to −0·77, P < 0·01) than the total number of Gag-specific CD8⁺ cells (r = 0·44–0·85, P ≤ 0·02). The Env/Gag ratio performed better than CD38 and HIV-RNA in logistic regression analysis predicting CD4 change rate as a measure of progression. In conclusion, HIV-specific CD8⁺CD107a⁺ Env/Gag response ratio was a stronger predictor for progression than CD38 and HIV-RNA. The Env/Gag ratio may reflect the balance between possibly beneficial (Gag) and detrimental (Env) CD8⁺ T cell responses and should be explored further as a progression marker.     

Relationship between T cell receptor clonotype and PD-1 expression of tumor-infiltrating lymphocytes in colorectal cancer

Adoptive T cell therapy using tumor-specific T cells or TCR-modified T cells is a promising next-generation immunotherapy. The major source of tumor-reactive T cells is PD-1⁺ tumor-infiltrating lymphocytes (TILs). In contrast, PD-1⁻ TILs have received little attention. Here, we analyzed the TCR-β repertoires of PD-1⁻ and PD-1⁺ CD8⁺ TILs derived from colorectal cancer and breast cancer. Approximately 40–60% of the PD-1⁺ population consisted of oligoclonal populations in both colorectal cancer and breast cancer. In contrast, approximately 37% of the PD-1⁻ population consisted of an oligoclonal population in colorectal cancer, whereas 14% of them were oligoclonal in breast cancer. In colorectal cancer, the TCR repertoires of PD-1⁻CD8⁺ TILs and PD-1⁺CD8⁺ TILs hardly overlapped. Interestingly, clonally expanded CD8⁺ TILs in primary tumors and the metastases expressing the same clonotypic TCR showed the same phenotype regarding the PD-1-expression. These results suggest that the intrinsic properties of TCRs determine the fate of TILs in terms of whether they become PD-1⁺ or PD-1⁻ in the tumor microenvironment. Further functional analysis of TCRs in TILs will allow us to better understand the regulatory mechanisms for PD-1 expression on TILs and may contribute to tumor immunotherapy.     

Increased CD4+CXCR5+T follicular helper cells in diabetic nephropathy

Background: T follicular helper (Tfh) cells are known to regulate humoral immune response. In this study we examined the correlation of different subsets of peripheral blood Tfh cells in patients with diabetic nephropathy (DN). Methods: A total of 23 DN patients and 15 healthy controls (HC) were investigated for various subsets of Tfh cells by flow cytometry. The molecules ICOS⁺, PD-1⁺, CD28⁺, CD154⁺, IL-21⁺, IFN-γ⁺, IL-4⁺, IL-17⁺ Tfh cells were examined. The subsets of B cells were investigated by flow cytometry. The levels of 24?h urinary protein and estimated glomerular filtration rate (eGFR) were calculated. A potential correlation between the number of different subsets of Tfh cells, B cells and DN, was assessed. Results: The circulating CD4⁺CXCR5⁺PD-1⁺, PD-1⁺CD154⁺, PD-1⁺CD28⁺, PD-1⁺IL-21⁺, PD-1⁺IL-4⁺, PD-1⁺-IL-17⁺-Tfh cell counts, CD38⁺CD19⁺, CD38⁺CD19⁺CD40⁺ B cells and plasma levels of IL-21 were significantly increased in DN patients (p?+CXCR5⁺PD-1⁺ Tfh cell counts negatively correlated with eGFR; Tfh cell counts positively correlated with 24?h urinary protein concentration in DN patients. Post-treatment, there was a significant reduction in the CD4⁺CXCR5⁺PD-1⁺ Tfh cell counts and its subsets, with a corresponding decrease in plasma levels of IL-6 and IL-17A (p?Conclusion: An increased number of CD4⁺CXCR5⁺PD-1⁺ Tfh cells were observed in DN patients, which may be new targets for intervention in DN.     

CD4+ CD25+ Treg regulate the contribution of CD8+ T-cell subsets in repopulation of the lymphopenic environment

Peripheral T‐cell expansion is of major relevance for immune function after lymphopenia. In order to promote regeneration, the process should result in a peripheral T‐cell pool with a similar subpopulation structure as before lymphopenia. We investigated the repopulation of the CD8⁺ central‐memory T cells (T_CM) and effector‐memory T cells (T_EM) pools after adoptive transfer of sorted CD8⁺ T cells from naïve, T_CM and T_EM subsets into T‐cell‐deficient hosts. We show that the initial kinetics of expansion are distinct for each subset and that the contribution to the repopulation of the CD8⁺ T‐cell pool by the progeny of each subset is not a mere function of its initial expansion. We demonstrate that CD4⁺CD25⁺ Treg play a major role in the repopulation of the CD8⁺ T‐cell pool and that CD8⁺ T‐cell subsets impact on each other. In the absence of CD4⁺CD25⁺ Treg, a small fraction of naïve CD8⁺ T cells strongly proliferates, correlating with further expansion and differentiation of co‐expanding CD8⁺ T cells. CD4⁺CD25⁺ Treg suppress these responses and lead to controlled repopulation, contributing decisively to the maintenance of recovered T_CM and T_EM fractions, and leading to repopulation of each pool with progeny of its own kind.     

Demonstration of identical expanded clones within both CD8+ CD28+ and CD8+ CD28− T cell subsets in HIV type 1-infected individuals

In HIV-1-infected individuals, the CD8⁺ CD28⁻ T cell subset is considerably expanded and is frequently the largest subset of T cells found in peripheral blood. It has been assumed, but not proven, that CD8⁺ CD28⁻ T cells derive from CD8⁺ CD28⁺ T cells in vivo. To further study the ontogeny of CD8⁺ CD28⁻ T cells, we have performed analyses of the complementarity determining region 3 (CDR3) of the TCRB of CD8⁺ CD28⁺ and CD8⁺ CD28⁻ T cells from the peripheral blood of HIV-1-infected individuals. When cells from the same individual were compared, expanded peaks in CDR3 length analysis within a given BV family were frequently observed at the same location in both CD8⁺ subsets ( p < 0.001). Sequencing of cDNA corresponding to dominant peaks revealed the presence of identical expanded CD8⁺ T cell clones within both the CD28⁺ and CD28⁻ subsets on eight of nine attempts. Our results show that CD8⁺ CD28⁺ and CD8⁺ CD28⁻ T cells are phenotypic variants of the same lineage, most likely evolving from CD8⁺ CD28⁺ to end-stage CD8⁺ CD28⁻ T cells.     

A novel peripheral CD4+CD8+ T cell population: Inheritance of CD8α expression on CD4+ T cells

In this study we show the inheritance of a CD4⁺CD8⁺ peripheral T cell population in the H.B15 chicken strain. A large proportion of αβ T cells in peripheral blood (20–40%), spleen (10–20%) and intestinal epithelium (5–10%) co-express CD4 and CD8α, but not CD8β. CD4⁺ CD8αα cells are functionally normal T cells, since they proliferate in response to mitogens and signals delivered via the αβT cell receptor as well as via the CD28 co-receptor. These cells induce in vivo a graft versus host-reaction, providing further evidence for their function as CD4⁺ T cells. The CD4⁺CD8αα T cell population was found in 75% of the first progeny and in 100% of further progenies, demonstrating that co-expression of CD4 and CD8 on peripheral T cells is an inherited phenomenon. In addition, cross-breeding data suggest a dominant Mendelian form of inheritance. The hereditary expression of CD8α on peripheral CD4⁺ T cells in chicken provides a unique model in which to study the regulation of CD4 and CD8 expression.     

The blockade of PD-1/PD-L1 pathway promotes the apoptosis of CD19+CD25+ Bregs and suppresses the secretion of IL-10 in patients with allergic rhinitis

PD-1/PD-L1 pathway is crucial to immune regulation by controlling the balance between T cell tolerance and activation. However, the association between PD-1/PD-L1 pathway and regulatory B cells has not been fully investigated in allergic rhinitis. In this study, we detected the number of peripheral CD19⁺CD25⁺ Bregs and the expression of IL-10 on this cell subset in healthy control and patients with allergic rhinitis using flow cytometry. Then, we evaluated the level of PD-L1 in CD19⁺CD25⁺ Bregs and investigated the correlation between PD-L1 and CD4⁺ follicular T helper cells. Finally, we studied the effects of anti–PD-L1 on the apoptosis of Bregs and the production of IL-10. Comparing with healthy controls, the percentage of CD19⁺CD25⁺ Bregs and the expression of IL-10 were both significantly decreased in AR group. In addition, the expression of PD-L1 on CD19⁺CD25⁺ Bregs was also lower in allergic rhinitis patients. Interestingly, a negative correlation was found between the expression of PD-L1⁺ Bregs and CD4⁺CXCR5⁺ follicular T helper cells. In vitro assay revealed that anti–PD-L1 promoted Bregs apoptosis and inhibited the expression of IL-10 in CD19⁺CD25⁺ Bregs. Collectively, these results suggest that PD-L1 expressed on CD19⁺CD25⁺ Bregs may be a potential regulator in the treatment of allergic rhinitis. Blockade of PD-1/PD-L1 pathway might be a valuable pathogenic target for allergic rhinitis through inhibiting the secretion of immunosuppressive cytokine and promoting CD19⁺CD25⁺ Bregs apoptosis.     

Origins and functional basis of regulatory CD11c+CD8+ T cells

Previously, we showed that CD11c defines a novel subset of CD8⁺ T cells whose in vivo activity is therapeutic for arthritis; however, the mechanisms directing their development, identity of their precursors, and basis of their effector function remain unknown. Here, we show that the novel subset develops from CD11c^surface?CD8⁺ T cells and undergoes robust expansion in an antigen‐ and 4‐1BB (CD137)‐dependent manner. CD11c⁺CD8⁺ T cells exist in naïve mice (<3%) with limited suppressive activity. Once activated, they suppress CD4⁺ T cells in vivo and in vitro. Suppression of CD4⁺ by CD11c⁺CD8⁺ T cells is related to an increase in IDO activity induced in competent cells via the general control non‐derepressible‐2 pathway. CD11c⁺CD8⁺ T cells are refractory to the effect of IDO but constrict in a novel 1‐methyl D ,L ‐tryptophan‐dependent mechanism resulting in reversal of their suppressive effects. Thus, our data uncover, for the first time, the origin, development, and basis of the suppressive function of this novel CD11c⁺CD8⁺ T‐cell subpopulation that has many signature features of Treg.     

Soluble PD-1 rescues the proliferative response of simian immunodeficiency virus-specific CD4 and CD8 T cells during chronic infection

Phenotypic and functional studies of the programmed death-1 (PD-1) molecule on CD4⁺ and CD8⁺ T cells were performed on peripheral blood mononuclear cells from uninfected and simian immunodeficiency virus (SIV)-infected rhesus macaques. These data demonstrated a rapid upregulation of PD-1 expression on tetramer-positive CD8⁺ T cells from MamuA.01⁺ SIV-infected macaques upon infection. Upregulation of PD-1 on total CD8⁺ T cells was not detectable. In contrast, CD4⁺ T-cell PD-1 expression was markedly higher in total CD4⁺ T cells during chronic, but not acute, infection and there was a correlation between the level of PD-1 expression on naive and central memory CD4⁺ T cells and the levels of viral loads. Such association was emphasized further by a marked decrease of PD-1 expression on tetramer-positive CD8 T cells as well as on CD4⁺ T cells on longitudinal samples collected before and after the initiation of antiretroviral therapy and downregulation of viral replication in vivo. Cloning of PD-1 and its two ligands from several non-human primate species demonstrated > 95% conservation for PD-1 and PD-L2 and only about 91% homology for PD-L1. Functional studies using soluble recombinant PD-1 protein or PD-1–immunoglobulin G fusion proteins induced marked increases in the SIV-specific proliferative responses of both CD4⁺ and CD8⁺ T cells from rhesus macaques. The results of these studies serve as a foundation for future in vivo trials of the use of rMamu-PD-1 to potentially enhance and/or restore antiviral immune responses in vivo.     

Expression of CTLA-4 (CD152) on human medullary CD4+ thymocytes

CTLA-4 (CD152) is a T cell surface receptor with sequence homology to the co-stimulatory molecule CD28. The molecule, which is essential for the inhibitory regulation of the immune response, becomes transiently expressed on mature T cells after stimulation in vitro. In situ, CTLA-4⁺ T cells are enriched in the light zones of the germinal centers in human peripheral lymphoid organs. In this study we have studied expression of CTLA-4 in human thymus in situ. CTLA-4 was expressed on about one third of CD4⁺/CD8^–/CD1^– medullary thymocytes. CTLA-4 was acquired by a subset of immature (CD1⁺) thymocytes and lost from the mature (CD1^–) subpopulation within 48 h of cell culture, suggesting that the expression on medullary thymocytes is transient. The demonstration of CTLA-4 on a substantial subpopulation of mature CD4⁺ thymocytes adds a new dimension to the understanding of this important molecule. When contemplating application of anti-CTLA-4 for therapy its potential influence on T cell maturation has to be taken into account. Received: 5 January 1998     

Age-related accumulation of LFA-1high cells in a CD8+CD45RAhigh T cell population

The differential expression of CD45 isoforms has been suggested as a marker for stages of post-thymic T cell development, that is, CD45RA+CD45R0^? T cells and CD45RA^?CD45R0⁺ T cells are supposed to be virgin and memory cells respectively. Recently, several adhesion molecules have been shown to be up-regulated on the cell surface of memory T cells, and have been suggested to serve as a memory marker. In this study, we investigated the levels of LFA-1 expression on T cells in various subpopulations defined by CD45 isoform expression in donors of various ages. In CD4⁺ T cells, the proportion of LFA-1^high cells among CD45RA^highCD45R0-T cells remained low in all age groups and did not show significant accumulation with age. CD4⁺CD45RA^?CD45R0^highTcells expressed LFA-1 at a higher level than CD4⁺CD45RA^highCD45R0^? T cells. Thus, the currently prevailing view that CD45RA and CD45R0 can be markers for virgin and primed cells was consistent with LFA-1 expression in CD4⁺ T cell population. In CD8⁺ T cells, however, CD45RA^highCD45R0^? T cells consisted of two distinct subpopulations, LFA-1^low and LFA-1^high cells, whereas CD45RA^?CD45R0^high T cells were almost exclusively LFA-1^high When CD29 expression was examined in place of LFA-1 expression, similar results were obtained; CD45RA^high CD45R0^? T cells consisted of two distinct subpopulations, CD29-^{to low} and CD^29high cells, while CD45RA-CD45R0^high T cells were mostly CD29^high. The proportion of LFA-1^high cells in the CD8+CD45RA^high T cell subpopulation increased significantly as a function of age (r = 0.9, p < 0.001). It ranged from 8% in a 14-year-old donor to 94% in a 79-year-old donor. Furthermore, the proportion of CD8⁺CD45RA^highLFA-1^high cells in the CD8⁺ T cell population increased significantly as a function of age (r = 0.85, p < 0.001). On the other hand, the proportion of LEA-1^high cells in CD8⁺CD45RA^? T cell subpopulation exceeded 90% in most donors irrespective of age. These results indicate that the CD8⁺CD45RA^highCD45R0^? T cell subpopulation contains a considerable number of LFA-1^high cells and CD29^high cells, phenotypically similar to previously activated cells. Thus, in terms of LFA-1 and CD29 expressions, the simple scheme that CD45RA is a marker of virgin cells is not applicable to the CD8⁺ T cell population.     

Comparison of lymphokine secretion and mRNA expression in the CD45RA+ and CD45RO+ subsets of human peripheral blood CD4+ and CD8+ lymphocytes

Flow cytometric analysis of human peripheral blood T lymphocytes demonstrated that the majority of the CD4⁺ cells were CD29⁺ or CD45RO⁺ “mature” cells while the CD8⁺ cells were primarily CD45RA⁺ “naive” cells. After an initial separation into CD4⁺ and CD8⁺ cells and a secondary separation into CD45 subsets, lymphokine secretion was assessed after phorbol 12-myristate 13-acetate and ionomycin or fixed anti-CD3 stimulation. Within the respective CD45 subsets, CD4⁺ cells produced more interleukin (IL)-2, IL-4, and IL-6; but the CD8⁺ cells secreted more interferon-γ and granulocyte/macrophage-colony-stimulating factor. Tumor necrosis factor-α secretion was similar in the matched CD45 subsets. Northern analysis revealed a parallel pattern of lymphokine mRNA expression in the four lymphocyte subsets. These results suggest that human CD8⁺ peripheral blood lymphocytes have a significant capacity to secrete lymphokines, and that the low lymphokine production observed in unseparated CD8⁺ cells reflects the higher percentage of less functional CD45RA⁺ cells.     

NK1.1+ CD4+ CD8- thymocytes with specific lymphokine secretion

CD4+8^? or CD4^?8⁺ thymocytes have been regarded as direct progenitors of peripheral T cells. However, recently, we have found a novel NK1.1⁺ subpopulation with skewed T cell antigen receptor (TcR) Vβ family among heat-stable antigen negative (HSA^?) CD4⁺8^? thymocytes. In the present study, we show that these NK1.1⁺ CD4+8^? thymocytes, which represent a different lineage from the major NK1.1^? CD4⁺8^? thymocytes or CD4⁺ lymph node T cells, vigorously secrete interleukin (IL)-4 and interfron (IFN)-γ upon stimulation with immobilized anti-TcR-αβ antibody. On the other hand, neither NK1.1^? CD4+8^?thymocytes nor CD4⁺ lymph node T cells produced substantial amounts of these lymphokines. A similar pattern of lymphokine secretion was observed with the NK1.1⁺ CD4⁺ T cells obtained from bone marrow. The present findings elucidate the recent observations that HSA^? CD4⁺8^? thymocytes secrete a variety of lymphokines including IFN-γ, IL-4, IL-5 and IL-10 before the CD4⁺8^? thymocytes are exported from thymus. Our evidence indicates that NK1.1⁺ CD4⁺8^? thymocytes are totally responsible for the specific lymphokine secretions observed in the HSA- CD4⁺8^? thymocytes.     

In Vivo CD3+CD25+ Lymphocyte Subpopulation Is Down-regulated Without Increased Serum-Soluble Interleukin-2 Receptor (sIL-2R) by Gonadotropin Releasing Hormone Agonist (GnRH-a)

PROBLEM: To test further whether the suppression of the CD3⁺CD25⁺ lymphocyte sub-population by gonadotropin-releasing hormone agonist (GnRH-a) is related to the change in levels of cytokines and soluble interleukin-2 receptor (sIL-2R). METHOD: Twenty-seven infertile patients were enrolled under the long protocol of GnRH-a agonist (buserelin acetate) and superovulation with gonadotropin from our IVF-ET program. Peripheral B cells, NK cells, CD4⁺ and CD8⁺ T cells and the expression of CD69, CD25, HLA-DR, and CD71 antigens on the T cells were serially examined by dual-color flow cytometry. Serum levels of cytokines and sIL-2R were measured. RESULTS: The B cells, NK cells, T cells, CD4⁺, CD8⁺ T cells, CD3⁺DR⁺, and CD3⁺CD71⁺ lymphocyte subpopulations were not changed after the use of GnRH-a. The CD25⁺ T cell subpopulation was significantly down-regulated, but the CD69⁺ T cell subpopulation was increased when the GnRH-a was used for approximately 2 wk. The serum levels of interleukin-lp (IL-1β), interleukin-2 (IL-2), interleukin-4 (IL-4), interferon-γ (IFN-γ), and sIL-2R were not changed. CONCLUSION: The GnRH-a had a transiently suppressive effect on CD25⁺ T cells, but a stimulatory effect on CD69⁺ T cells. However, the serum level of cytokines or sIL-2R did not change. These immunological modulations seems to be the result of interaction between GnRH-a and estrogen.     

Upregulation of Immune Checkpoint Molecules,PD-1 and LAG-3, on CD4+ and CD8+ T Cells after Gastric Cancer Surgery

Background

Surgery has been reported to suppress cell-mediated immunity; however, the detailed mechanisms responsible for this remain unclear. This study determined the expression of lymphocyte activation gene 3 (LAG-3) and programmed cell death 1 (PD-1) in lymphocytes following surgery for gastric cancer.

Methods

LAG-3 and PD-1 expression on both CD4+ and CD8+ T cells obtained pre- and post-operatively from gastric cancer patients were evaluated by multicolor flow cytometry.

Results

The total lymphocyte count decreased rapidly from preoperative levels, reaching a minimum on postoperative day 1 and remaining significantly decreased on days 3 and 7. PD-1⁺CD4⁺ T cells significantly increased, reaching a maximum on postoperative day 1 and remaining significantly elevated on day 3. PD-1⁺CD8⁺ T cells significantly increased and reached a maximum on day 7 before returning to the preoperative level on day 30. There were no statistically significant differences in the frequency of LAG-3⁺CD4⁺ or LAG-3⁺CD8⁺ T cells after surgery. There were significant positive correlations between PD-1 and LAG-3 expression on both CD4⁺ andCD8⁺ T cells.

Conclusion

PD-1 and LAG-3 expression on both CD4⁺ and CD8⁺ T cells was up-regulated and might be related to impaired cell-mediated immunity after surgery for gastric cancer.     

Circulating CD4+CD8+ T lymphocytes in patients with Kawasaki disease

We serially monitored cell surface antigen expression on mononuclear cells in peripheral blood isolated from patients with Kawasaki disease (KD), and found, for the first time, that a markedly increased number of CD4⁺CD8⁺ T lymphocytes was present in some of the patients (11 of the 24 cases). The cases of five of these 11 patients were complicated with coronary artery lesion (CAL); the 13 patients with normal numbers of CD4⁺CD8⁺ T lymphocytes did not have CAL. The patients' age, sex and grade of systemic inflammation evaluated by peripheral leucocyte count and serum C-reactive protein levels were not correlated to the number of CD4⁺CD8⁺ T lymphocytes. Other cell surface antigen characteristics of the CD4⁺CD8⁺ T lymphocytes included CD3⁺, CD45RA⁺, CD45RO⁺, CD16^?, and HLA-DR⁺. These results indicate that the surface antigen characteristics of the KD peripheral blood examined were the same as those of Epstein–Barr virus infection without CD45RA⁺. These findings provide useful information for the analysis of the pathogenesis of KD.     

MDSC subtypes and CD39 expression on CD8+ T cells predict the efficacy of anti-PD-1 immunotherapy in patients with advanced NSCLC

The major suppressive immune cells in tumor sites are myeloid derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and Treg cells, and the major roles of these suppressive immune cells include hindering T-cell activities and supporting tumor progression and survival. In this study, we analyzed the pattern of circulating MDSC subtypes in patients with non-small cell lung cancer (NSCLC) whether those suppressive immune cells hinder T-cell activities leading to poor clinical outcomes. First, we verified PMN-MDSCs, monocytic-MDSCs (M-MDSCs), and Treg cells increased according to the stages of NSCLC, and MDSCs effectively suppressed T-cell activities and induced T-cell exhaustion. The analysis of NSCLC patients treated with anti-PD-1 immunotherapy demonstrated that low PMN-MDSCs, M-MDSCs, and CD39⁺CD8⁺ T cells as an individual and all together were associated with longer progression free survival and overall survival, suggesting PMN-MDSCs, M-MDSCs, and CD39⁺CD8⁺ T cells frequencies in peripheral blood might be useful as potential predictive and prognostic biomarkers.