Lymphocyte Recovery After Breast Cancer Treatment and Mindfulness-Based Stress Reduction (MBSR) Therapy

2011 ◽  
Vol 15 (1) ◽  
pp. 37-47 ◽  
Author(s):  
Cecile A. Lengacher ◽  
Kevin E. Kip ◽  
Janice Post-White ◽  
Shirley Fitzgerald ◽  
Cathy Newton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Treatment ◽  
Nk Cells ◽  
Stress Reduction ◽  
Lymphocyte Subsets ◽  
Immune Recovery ◽  
T Helper ◽  
Mindfulness Based Stress Reduction

Objectives:This randomized controlled trial was conducted to examine immune recovery following breast cancer (BC) therapy and evaluate the effect of mindfulness-based stress reduction therapy (MBSR) on immune recovery with emphasis on lymphocyte subsets, T cell activation, and production of T-helper 1 (Th1; interferon [IFN]-γ) and T-helper 2 (Th2; interleukin-4 [IL-4]) cytokines.Method:Participants who completed the study consisted of 82 patients diagnosed with Stage 0–III BC, who received lumpectomy and adjuvant radiation ± chemotherapy. Patients were randomized into an MBSR(BC) intervention program or a control (usual care) group. Immune cell measures were assessed at baseline and within 2 weeks after the 6-week intervention. The numbers and percentages of lymphocyte subsets, activated T cells, and Th1 and Th2 cells in peripheral blood samples were determined by immunostaining and flow cytometry.Results:Immune subset recovery after cancer treatment showed positive associations with time since treatment completion. The B and natural killer (NK) cells were more susceptible than T cells in being suppressed by cancer treatment. Women who received MBSR(BC) had T cells more readily activated by the mitogen phytohemagglutinin (PHA) and an increase in the Th1/Th2 ratio. Activation was also higher for the MBSR(BC) group if <12 weeks from the end of treatment and women in MBSR(BC) <12 weeks had higher T cell count for CD4+.Conclusion:MBSR(BC) promotes a more rapid recovery of functional T cells capable of being activated by a mitogen with the Th1 phenotype, whereas substantial recovery of B and NK cells after completion of cancer treatment appears to occur independent of stress-reducing interventions.

Therapeutic effect of local Interleukin-15 with radiotherapy in breast cancer.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 158-158
Author(s):  
Elena Garcia Martinez ◽  
Karsten A Pilones ◽  
Joseph Aryankalayil ◽  
Silvia Formenti ◽  
Sandra Demaria
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Therapeutic Effect ◽  
Tumor Immunity ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Control ◽  
Complete Regression ◽  
Growth And Survival

158 Background: Interleukin (IL)-15 is a key regulator of T cell homeostasis with activity in cancer and a favorable toxicity profile compared to IL-2. IL-15 stimulates the proliferation and effector differentiation of CD8+T cells, and the proliferation and activation of natural killer (NK) cells. We observed IL-15 upregulation by gene arrays in radiotherapy (RT)-treated TSA mouse breast cancer, suggesting that it may play a role in RT-induced anti-tumor immunity. However, the upregulation was modest prompting us to test the hypothesis that administration of IL-15 may enhance in situ vaccination by RT. Methods: BALB/c mice with established poorly immunogenic TSA tumors were sham-treated, treated with tumor-targeted RT (8GyX3 days), IL-15 given peri-tumorally (2 ug/mouse/day for 10 days) starting on the first day of RT, and RT+IL-15, and monitored for tumor growth and survival. Tumor infiltrating lymphocytes (TIL) were analyzed by flow cytometry and immunostaining. In some experiments, Batf3-/-mice were used as tumor recipient. Results: IL-15 by itself was ineffective, but it significantly increased tumor control by RT (p=0.0007, RT versus RT+IL-15) leading to complete responses in 50% of the mice, most of them durable. Analysis of TILs showed significantly increased NK cells (CD45+ CD3- DX5+) in tumors treated with RT+IL-15 (p<0.0004 versus sham-treated; p<0.02 versus RT). NK cells were also more activated as indicated by expression of CD122 and CD137. Depletion of NK cells completely abrogated the therapeutic effect of the combination, while CD8 T cell depletion reduced tumor control and rate of complete regression. Interestingly, Batf3-/- mice, which lack CD103+ DCs, showed reduced response to RT+IL-15 compared to WT mice. Conclusions: Data suggest that local IL-15 with RT is an effective strategy to induce anti-tumor immunity to poorly immunogenic breast cancer. NK cells are critical mediators of the response, and may act by both killing tumor cells and promoting priming of CD8 T cells. Experiments are ongoing to determine the mechanisms of durable complete responses. <footer>Acknowledgments: IL-15 was provided by NCI BRB. Garcia-Martinez E was supported by GEICAM grant.</footer>

Abstract P216: Inhibition Of T Cell Activation In Response To Placental Ischemia During Pregnancy Improves Hypertension And Activation Of Natural Killer Cells

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Nathan Campbell ◽  
Evangeline M Deer ◽  
Lorena M Amaral ◽  
Kristen Reeve ◽  
Sarah Fitzgerald ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
T Helper Cells ◽  
Cell Activation ◽  
T Helper ◽  
Placental Ischemia

Preeclampsia (PE), new onset hypertension during pregnancy, is the leading cause of death and morbidity world-wide for the mother and fetus during pregnancy. The Reduced Uterine Perfusion Pressure Rat Model of PE (RUPP) exhibits many characteristics of PE including hypertension, suppressed regulatory T cells (T RegS ) associated with increased CD4+ T cells and B cells secreting agonistic autoantibodies to the AngII receptor (AT1-AA). We have previously shown that blockade of T-helper cells improves blood pressure and lowers AT1-AA secretion. A potential mechanism for the decreased blood pressure is decreased cytolytic natural killer (cNK) cells. Abatacept (Aba) is a fusion molecule designed to inhibit T cell co-stimulation in response to antigens and is used to treat autoimmune diseases. We hypothesize that treatment with Aba will prevent the activation of T-helper cells and therefore lower AT1-AA as a mechanism leading to less cNK cells in response to placental ischemia in RUPP rats. Aba was given on day 13 via the jugular vein. On day 19, blood and tissues were collected, blood pressure (MAP), pup weight, and NK cells were measured by flow cytometry in the blood and placenta. A one-way ANOVA was used for statistical analysis. On GD19, MAP significantly increased in RUPP 119±2 mmHg (n=7, p<0.05) compared to NP controls 102±2 mmHg (n=7) and was normalized with Aba (100±2 mmHg (n=10, p<0.05). Compared to the NP controls (2.2±0.06, n=7), pup weight significantly decreased in RUPP (2±0.08, n=7, p<0.05) but was 2± 0.07, with Aba (n=10). Circulating and placental total NK cells were 32±5, 44±13, % gate in NP rats (n=7), 59±4, 60±16 % gate in RUPP rats (n=7, p<0.05; n=4), which significantly decreased to 40±6, 28±8 % gate with Aba (n=10, p<0.05; n=11). Our findings indicate that prevention of T cell activation lowers total NK cell number and blood pressure in response to placental ischemia of pregnancy.

Alloreactive Natural Killer Cells Rebuild Adaptive Immunity to Infections after Haploidentical Hematopoietic Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3210-3210
Author(s):  
Loredana Ruggeri ◽  
Emanuela Burchielli ◽  
Katia Perruccio ◽  
Marusca Capanni ◽  
Martin Stern ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Acute Leukemia ◽  
Nk Cells ◽  
Leukemic Cells ◽  
Immune Recovery ◽  
Clinical Issue ◽  
Cell Immunity ◽  
Hematopoietic Transplantation

Abstract Transplantation of peripheral blood hematopoietic cells from HLA haplotype-mismatched family members is a therapeutic strategy for patients with high-risk acute leukemia who need transplantation and do not have matched donors. As T cell alloreactions cause lethal GvHD in mismatched transplants, only T cell-depleted hematopoietic grafts can be used. In adults, because of declining thymic function, immune-recovery originates from expansion of the mature T cells infused with the graft. In T cell depleted mismatched transplant immune recovery is hindered by the paucity of the starting T-cell population. Slow recovery of functional T cell immunity to pathogens is responsible for 35% infection-related mortality which remains the most pressing clinical issue. In murine MHC-haploidentical bone marrow transplant models we demonstrated donor-versus-recipient alloreactive NK cells ablate recipient-type lympho-hematopietic cells such as leukemic cells, the T cells that cause rejection and the antigen-presenting cells which trigger GvHD. Consequently mismatched T cell-replete transplants can be performed without GvHD (Ruggeri et al., Science 2002). Unexpectedly, in recent experiments, we observed alloreactive NK cells hastened immune-reconstitution. Pre-transplant infusion of alloreactive NK cells promoted brisk recovery of donor B and T cell precursors which matured correctly and of donor DCs. Rapidly reconstistuting DCs were crcuicial in protecting mice from infectious challenges. We next demonstrated:interaction between alloreactive NK cells and NK-susceptible recipient DCs alone was responsible for immune-rebuilding,NK conditioned mice remain receptive to accelerated immune rebuilding even when transplanted a week after NK conditioning, therefore the NK-DC interaction appears to release an as yet unknown immune-rebuilding factor which acts upon bone marrow and thymus microenvironements stably over time,quantitative PCR on bone marrow and thimus of NK conditioned mice shows several-fold increased expression of cytokines implicated in B, T and myeloid cell maturation, such as IL-7 and c-Kit ligand;the accelerated immune rebuilding effect can be reproduced by conditioning mice with the infusion of NK:DC co-culture supernatants. These observation prompted an analysis of infectious mortality in 178 acute leukemia patients who received haploidentical transplant at our Center. Transplantation from KIR ligand-mismatched (i.e., NK alloreactive) donors, in addition to controlling AML relapse, offers statistically significant protection from infectious mortality in AML and ALL patients. Studies are in progress to identify “immune rebuilding factor(s)”, produced in consequence of the interaction between donor alloreactive NK and recipient DCs, in the hope they might be exploited to boost immune-recovery and help reduce infection mortality after haploidentical hematopoietic transplantation.

CAR-Engineered T Cells Specific for the Elotuzumab Target SLAMF7 Eliminate Primary Myeloma Cells and Confer Selective Fratricide of SLAMF7+ Normal Lymphocyte Subsets

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 115-115 ◽  
Author(s):  
Sophia Danhof ◽  
Tea Gogishvili ◽  
Silvia Koch ◽  
Martin Schreder ◽  
Stefan Knop ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cell Lines ◽  
Cd8 T Cells ◽  
Lymphocyte Subsets ◽  
Normal Lymphocyte ◽  
Car T Cells ◽  
Car T ◽  
T Cell Lines

Abstract Background: SLAMF7 (CS1, CD319) is uniformly and highly expressed in multiple myeloma (MM) where it promotes adhesion and survival of malignant plasma cells (mPCs) in the bone marrow niche. It is absent on normal solid organ tissues but known to be expressed on lymphocyte subsets (T, B and NK cells). Clinical evaluation of the anti-SLAMF7 monoclonal antibody (mAb) Elotuzumab (huLuc63) has resulted in marked reversible lymphodepletion and conferred potent anti-MM efficacy in combination therapy. Here, we evaluated the potential to generate SLAMF7-directed chimeric antigen receptor (CAR) modified T cells from previously treated MM patients and analyzed their potency against autologous mPCs as well as fratricidal activity against normal lymphocyte subsets. Methods: Flow cytometric analyses for SLAMF7 expression on mPCs and normal lymphocyte subsets of MM patients (n=67) and healthy donors (n=20) was performed using specific mAbs and matched isotype controls. A SLAMF7-specific CAR was constructed using the VH/VL targeting domains of mAb huLuc63, fused to an Ig-Fc spacer and a signaling module of CD3ζ and CD28. Lentiviral gene transfer was performed into CD3/CD28-bead stimulated bulk CD4+ and CD8+ T cells of MM patients (n=7). CAR transgene positive T cells were enriched using an EGFRt transduction marker and expanded for functional analyses. Results: We confirmed high SLAMF7 expression levels on mPCs in all analyzed samples and detected SLAMF7 expression on a fraction of normal lymphocytes obtained from peripheral blood of MM patients, including naïve and memory CD4+ (95% CI: 33-59%) and CD8+ T cells (75-95%), B cells (25-35%) and NK cells (94-98%). Remarkably, the proportion of SLAMF7+ cells was significantly higher in MM patients compared to healthy donors in all corresponding lymphocyte subsets (p<0.05). Despite high level SLAMF7 expression on the input T cell population, functional CD4+ and CD8+ T cells expressing the SLAMF7-CAR could be readily generated in all 7 MM patients, and expanded to therapeutically relevant doses in a single expansion cycle following enrichment (>107 cells). We analyzed the kinetics of SLAMF7 expression on CD4+ and CD8+ CAR T cells during the manufacturing process and detected rapid disappearance of SLAMF7+ T cells in T cell lines modified with the SLAMF7-CAR. By contrast unmodified T cells and T cell lines expressing a CD19-CAR retained a significant proportion of SLAMF7+ T cells, suggesting that expression of the SLAMF7-CAR induced killing of SLAMF7+ T cells. In vitro functional testing of SLAMF7-CAR CD4+ and CD8+ T-cell lines confirmed potent specific lysis of SLAMF7+ MM cell lines including MM1.S and OPM-2 and stable SLAMF7-transfectants of K562, as well as antigen specific IFNγ secretion and productive proliferation. In a flow cytometry based cytotoxicity assay, co-incubation of mPCs with autologous (or allogeneic) SLAMF7-CAR T cells resulted in elimination of >90% of mPCs after a 4-hour incubation period, whereas CD19-CAR or unmodified T cells had no discernible effects. Moreover, in an in vivo xenograft MM model (NSG/MM1.S) a single administration of SLAMF7-CAR T cells resulted in complete MM clearance and long-term survival, whereas mice treated with CD19-CAR or unmodified T cells rapidly expired from progressive disease. Finally, we analyzed the fratricidal potential of SLAMF7-CAR T cells to predict hematologic toxicities that might occur in a clinical setting. Co-incubation of purified CD4+ and CD8+ primary T cells, B cells and NK cells with SLAMF7-CAR T cells resulted in rapid and specific elimination of only SLAMF7+ subsets, whereas SLAMF7- cells remained viable and functional as confirmed for CD4+ and CD8+ T cells by inducible IFNγ secretion. Conclusion: Our data demonstrate that SLAMF7-specific CAR T cells can be reproducibly generated from MM patients and exert remarkable anti-myeloma efficacy in pre-clinical models in vitro and in vivo. Lymphocytic fratricide does not preclude the manufacture of SLAMF7-CAR T cells but might be associated with acute (cytokine storm) or chronic (viral infections) side effects in a clinical setting. However, such toxicities may be prevented e.g. by preparative lymphodepletion and antiviral prophylaxis and enable the implementation of SLAMF7-CAR T cell therapy as a safe and effective modality in the treatment of MM. Disclosures Knop: Celgene Corporation: Consultancy. Einsele:Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals The Transcription Factor Interferon Regulatory Factor 1 (IRF-1) Is Important during the Maturation of Natural Killer 1.1+ T Cell Receptor–α/β+ (NK1+ T) Cells, Natural Killer Cells, and Intestinal Intraepithelial T Cells

1998 ◽  
Vol 187 (6) ◽  
pp. 967-972 ◽  
Author(s):  
Toshiaki Ohteki ◽  
Hiroki Yoshida ◽  
Toshifumi Matsuyama ◽  
Gordon S. Duncan ◽  
Tak W. Mak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Receptor ◽  
Lymphocyte Subsets ◽  
Cell Receptor ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1

In contrast to conventional T cells, natural killer (NK) 1.1+ T cell receptor (TCR)-α/β+ (NK1+T) cells, NK cells, and intestinal intraepithelial lymphocytes (IELs) bearing CD8-α/α chains constitutively express the interleukin (IL)-2 receptor (R)β/15Rβ chain. Recent studies have indicated that IL-2Rβ/15Rβ chain is required for the development of these lymphocyte subsets, outlining the importance of IL-15. In this study, we investigated the development of these lymphocyte subsets in interferon regulatory factor 1–deficient (IRF-1−/−) mice. Surprisingly, all of these lymphocyte subsets were severely reduced in IRF-1−/− mice. Within CD8-α/α+ intestinal IEL subset, TCR-γ/δ+ cells and TCR-α/β+ cells were equally affected by IRF gene disruption. In contrast to intestinal TCR-γ/δ+ cells, thymic TCR-γ/δ+ cells developed normally in IRF-1−/− mice. Northern blot analysis further revealed that the induction of IL-15 messenger RNA was impaired in IRF-1−/− bone marrow cells, and the recovery of these lymphocyte subsets was observed when IRF-1−/− cells were cultured with IL-15 in vitro. These data indicate that IRF-1 regulates IL-15 gene expression, which may control the development of NK1+T cells, NK cells, and CD8-α/α+ IELs.

scholarly journals Identification of Lymphocyte Subsets Associated with Outcomes in Patients with Hematological Malignancy Following Allogeneic Stem Cell Transplantation: A Single Institute Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2115-2115
Author(s):  
Taiki Ando ◽  
Yasufumi Ishiyama ◽  
Takayoshi Tachibana ◽  
Masatsugu Tanaka ◽  
Heiwa Kanamori ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Nk Cells ◽  
Immune Reconstitution ◽  
Lymphocyte Subsets ◽  
Chronic Gvhd ◽  
T Cell Subsets ◽  
Transplant Outcome ◽  
Cell Sources

Abstract Background: Immune reconstitution after allogeneic stem cell transplantation (SCT) is a complicated process influenced by factors such as preconditioning regimens, graft-versus-host disease (GVHD) prophylaxis, and grafts. We studied the association between the kinetics of lymphocyte subsets and transplant outcome to clarify the differences in immune reconstitution after hematopoietic cell transplantation according to stem cell sources and its clinical significance. Patients and Methods: Clinical data were collected from patients' medical charts at Kanagawa Cancer Center, Yokohama, Japan. Patients with hematological malignancies aged ≥18 years old who underwent SCT between April 2009 and December 2017 were initially selected. Those who died or experienced disease relapse before day 100 post SCT were excluded. We measured absolute lymphocyte count (ALC) and lymphocyte subsets by flow cytometry with antibodies against CD2, CD3, CD4, CD8, CD11b, CD11c, CD16, CD25, CD29, CD56, CD57, CD45RA, and CD45RO on days 100, 180, 365, and 730 post SCT. Results: The final cohort included 314 patients (acute leukemia, n = 249; myelodysplastic syndrome, n = 44; chronic myelogenous leukemia, n = 9; malignant lymphoma, n = 6; and others, n = 6). The median age was 51 (range: 18- 69) years, with 184 males and 130 females. The disease risk at transplantation was standard in 209 and high in 105 patients. Myeloablative preconditioning was administered to 114 and reduced-intensity preconditioning to 200 patients. Bone marrow transplantation (BMT), peripheral blood SCT (PBSCT), and cord blood transplantation (CBT) were performed in 121, 57, and 136 patients, respectively. A calcineurin inhibitor with short-term methotrexate was mainly used for GVHD prevention. The median follow-up of surviving patients was 869 (range: 103-3074) days. The 2-year overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) in BMT, PBSCT, and CBT were 62%, 68%, and 76% (P = 0.023); 33%, 38%, and 27% (P = 0.068); and 17%, 16%, and 13% (P = 0.82); respectively. The 2-year cumulative incidence of chronic GVHD was 43% in BMT, 45% in PBSCT, and 28% in CBT (P = 0.027). There were significant differences between lymphocyte subset recovery and stem cell sources (Table). ALC; CD20+ B cell; CD4+, CD4+CD29+, CD4+CD45RO+, CD4+CD45RO− , and CD4+CD45RA+ T cell subsets; and CD3−CD56+ and CD16+CD57− natural killer (NK) cell subsets were significantly elevated in CBT compared with BMT and PBSCT at day 100 post SCT. Conversely, CD8+CD11b+ and CD8+CD11b− T cell subsets and CD3+CD56+ NKT cells were significantly lower in CBT than in BMT and PBSCT on day 100. Univariate analysis revealed that lymphocyte subsets exhibiting higher levels of CD20+ B cell; CD16+CD57− and CD3−CD56+ NK cells; and CD4+CD25+, CD4+CD29+, CD4+CD45RA+, CD8+CD11b+, and CD8+CD11b− T cell subsets at day 100 were associated with a better 2-year OS. There were strong correlations with a lower CIR and higher CD16+CD57+ and CD16+CD57− NK cell levels . A higher incidence of chronic GVHD was associated with lower levels of CD16+CD57− NK cells and CD4+CD25+ T cells and with higher levels of CD8+CD11b+ T cells and CD8+CD11b− and CD3+CD56+ NKT cells. Further, a lower NRM correlated with higher levels of CD20+ B cells and CD8+CD11b− T cells. The lymphocyte subsets were used for multivariate analysis. Favorable factors for better OS were higher levels of CD16+CD57− NK cells [hazard ratio (HR), 0.62; 95% confidence index (CI), 0.38-0.81; P = 0.024] and CD20+ B cells (HR, 0.56; 95% CI, 0.31-0.0.98; P = 0.048). Prognostic factors for lower CIR were higher levels of CD16+CD57+ NK cells (HR, 0.51; 95% CI, 0.27-0.95; P = 0.034) and CD16+CD57− NK cells (HR, 0.52; 95% CI, 0.28-0.99; P = 0.048). A lower incidence of NRM was associated with higher levels of CD8+CD11b− T cells (HR, 0.18; 95% CI, 0.08-0.39; P < 0.001) and CD20+ B cells (HR, 0.24; 95% CI, 0.08-0.70; P = 0.0088). High levels of CD8+CD11b+ T cells were an independent predictor for a higher incidence of chronic GVHD (HR, 2.38; 95% CI, 1.22-4.95; P = 0.012). Conclusions: The distinct differences in immune reconstitution according to stem cell sources and lymphocyte subset analysis at day 100 post SCT are useful for predicting transplant outcome. Furthermore, the results suggest that characteristic immune recovery in CBT positively affects transplant outcome. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Rise in Percentages of Circulating Lymphocyte Subsets Correlates With Acute Rejection in Liver Transplant Recipients

2021 ◽  
Author(s):  
Fei Pan ◽  
Shuang Cao ◽  
Xian-Liang Li ◽  
Wen-Li Xu ◽  
Han Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Acute Rejection ◽  
Liver Transplant ◽  
Nk Cells ◽  
Lymphocyte Subsets ◽  
T Cell Subsets ◽  
Transplant Recipients ◽  
Nk T Cells ◽  
Liver Transplant Recipients

Abstract Background: Little is known about the shift of circulating lymphocyte subsets following liver transplantation and thus, its relationship with acute rejection. Methods: Liver transplant recipients were enrolled to assess the effect of primary liver diseases, gender, age, and follow-up periods on the shift of circulating lymphocyte subsets. Moreover, patients with rejection were paired to assess the effect of the shift on rejection.Results: When compared with patients from the middle-term group (29-180 d) and the long-term group (>180 d), patients from the short-term group (< 29 d) had the lowest absolute counts of T cell subsets, NK cells and NK T cells, and the lowest percentages of T cell subsets, B cells, NK cells and NK T cells but the highest percentage of DC. However, other factors did not affect circulating lymphocyte subsets. Percentages of T cells, CD4+T cells, B cells and NK T cells were higher in patients with acute rejection while percentages of T cell subsets and NK cells decreased after anti-rejection treatment. The percentage of NK T cells was identified to be the only independent predictor for acute rejection. The predicted probability was calculated using binary logistic with the area under the curve of 0.89, which had a sensitivity of 70.6% and a specificity of 94.1% at a cut-off value of 0.69.Conclusions: Circulating lymphocyte subsets gained a global recovery over the post-transplant period, leading to a sharp rise in percentages of circulating lymphocyte subsets, which was in close relation to the occurrence of acute rejection.

scholarly journals PTEN loss correlates with T cell exclusion across human cancers

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ziying Lin ◽  
Lixia Huang ◽  
Shao Li Li ◽  
Jincui Gu ◽  
Xiaoxian Cui ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Helper Cells ◽  
Pi3k Pathway ◽  
T Helper ◽  
Immune Microenvironment ◽  
Pten Loss ◽  
Pathway Activation ◽  
Tumor Types ◽  
T Cell Exclusion

Abstract Background Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood. Methods Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation. Results We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy. Conclusion These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.

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