Absolute CD4+ T-Cell Count Predicts Survival in Diffuse Large B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3053-3053 ◽  
Author(s):  
Yoshiharu Kusano ◽  
Yasuhito Terui ◽  
Kengo Takeuchi ◽  
Anna Takahashi ◽  
Norihito Inoue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Count ◽  
Peripheral Blood ◽  
Cd8 T Cell ◽  
Tumor Burden ◽  
Cd4 T Cell ◽  
Stage Iii ◽  
Cell Ratio

Abstract Introduction Tumors deregulate immunological antitumor response, resulting in survival of tumor cells, which implicate the existence of immunological tolerance to tumors.CD4+ T cells activate tumor-specific cytotoxic CD8+ T cells via cytokines and they also can eliminate cancer in the absence of CD8+ T cell. Absolute CD4+ T-cell count(ACD4C)in biopsied specimen is known to correlate with therapeutic outcomes in DLBCL. In patients with solid cancer, CD4+ T cells decrease in the peripheral blood, whereas regulatory T cells (Tregs) increase in the peripheral blood.Tregshave a role to reduce antibody dependent cellular toxicity (ADCC) of rituximab against CD20+ B-cell malignancies. On the other hand,we and othersknow that absolute lymphocyte count in peripheral blood can predict survival of diffuse large B-cell lymphoma (DLBCL). It has been indefinite, however, which lymphocyte including CD4+ T cells in peripheral blood reflect the prognosis of DLBCL. Method We enrolled patients who were diagnosed with de novo DLBCL from 2006 until 2013, received R-CHOP, and followed up at Cancer Institute Hospital, Tokyo, Japan. We had measured absolute lymphocyte count, T-cell ratio, CD4+ T-cell ratio, and CD8+ T-cell ratio in these patients using pretreatment blood samples. Data were collected prospectively and recorded into a computerized database. All patientsgave written informed consent allowing the use of their medical record. The optimal cut-off values were made based on its utility as a marker for death using box plot, clinical important value from references, and receiver operating characteristic curve. Differences between the results of comparative tests were considered significant if the two-sided P value was less than 0.05. Results A total of 355 patients were diagnosed with de novo DLBCL.Baseline characteristics were following: median age was 65 (range 20-89), Patients aged over 60 were 243 (68%), male to female ratio was 1.2, ECOG PS ≥ 2 of 19 (5%), elevated LDH of 152 (43%), low ACD4C (< 350 x 106 /l) of 119 (34%), low ACD8C (< 300 x 106 /l) of 144 (41%), CD5+ DLBCL of 38 (11%), Ann Arbor stage III/IV of 145 (41%), and involved extranodal sites ≥ 2 of 93 (26%). Germinal center B cell (GCB) DLBCL was seen in 167 (53%), non-GCB DLBCL was seen in 148 (47%). Patients without evidence of death (n = 282) at last follow-up had a higher ACD4C (≥ 350 x 106 /l) at diagnosis than those with death (n = 73) (P < 0.0001). There was also markedly difference in absolute CD8+ T-cell count, but no difference in absolute B-cell count. At the median follow-up of 57 months, Kaplan-Meier method estimated that 5-year PFS was 78.1% in the high ACD4C group and 62.0% in the low ACD4C group (Figure 1A, log-rank P < 0.001), whereas 67.4% in the high ACD8C group and 41.6% in the low ACD8C group (P = 0.01). Furthermore, 5-year OS was 83.6% in the high ACD4C group and 64.5% in the low ACD4C group (Figure 1B, log-rank P < 0.001), whereas 56.2% in the high ACD8C group and 36.1% in the low ACD8C group (P < 0.01). An ACD4C < 350 x 106 /l was identified as an adverse prognostic marker in DLBCL by Cox hazard model (hazard ratio 1.9, P = 0.01). In addition, CD5+ DLBCL, PS ≥ 2, stage III/IV, and non-GCB DLBCL were identified as low ACD4C. Age > 60, extranodal diseases ≥ 2, and elevated LDH were not identified in this study. ACD4C had negative correlation with tumor burden, which was shown by Pearsonfs coefficient (correlation with LDH; r = -0.24, P < 0.0001) and Studentfs t-test (correlation with stage; P < 0.0001). Interestingly, low ACD4C affected OS only in the stage III/IV, non-GCB DLBCL, and high-IPI groups (fisherfs exact test P < 0.01). Baseline characteristics of the low ACD4C group showed higher rate of stage III/IV (P < 0.001), elevated LDH (P < 0.01), extranodal disease ≥ 2 (P < 0.001), soluble IL-2 receptor > 2000 U/l (P < 0.001), low serum albumin (P = 0.001), and beta2 microglobulin > 2 mg/dl (P < 0.001). Conclusion This study demonstrates that ACD4C had a negative correlation with tumor burden and low ACD4C at diagnosis made worse prognosis of patients with DLBCL, in particular, those who had high tumor burden, non-GCB, or high IPI at diagnosis, suggestingTregsmight increase in peripheral blood in the low ACD4C group and might impair the ADCC of rituximab. Figure 1 Figure 1. Disclosures Terui: Yanssen: Honoraria. Mishima:Chugai: Consultancy. Nishimura:Chugai: Consultancy. Yokoyama:Chugai: Consultancy. Hatake:Meiji-Seika: Consultancy; Kyowa Kirin: Honoraria, Research Funding; Chugai: Research Funding; Otsuka: Consultancy.

scholarly journals High CD4+ T-Cell/B-Cell Ratio in the Paranasal Sinus Mucosa of Patients with Eosinophilic Chronic Rhinosinusitis

2020 ◽  
Author(s):  
Akiko Inoue ◽  
Yuriko Tanaka ◽  
Shinya Ohira ◽  
Kentaro Matsuura ◽  
Motonari Kondo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Chronic Rhinosinusitis ◽  
Paranasal Sinus ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Eosinophil Infiltration ◽  
Cell Ratio ◽  
Sinus Mucosa

Abstract Introduction Chronic rhinosinusitis (CRS) is commonly classified based on the presence or absence of nasal polyps (NPs). Eosinophil infiltration is observed in NPs of patients in Western countries. In contrast, in East Asian countries, including Japan, CRS with NPs (CRSwNP) is subdivided based on the presence (eosinophilic CRS [ECRS]) or absence (non-eosinophilic CRS [NECRS]) of eosinophils in NPs. However, detailed analyses of other immune cells, such as lymphocytes, in NPs have not been performed. Therefore, clarification of the types of cells that infiltrate NPs is important to understand CRS pathogenesis. Objectives We analyzed the lymphocytes that infiltrate the paranasal sinus mucosa of ECRS and NECRS patients. Methods Eighteen patients with CRSwNP participated in this study, out of whom 6 were NECRS patients, and 12 were ECRS patients. The mucosa specimens, collected from patients during sinus surgeries, were subjected to collagenase treatment to prepare single cell suspensions. Then, mononuclear cells were isolated, and CD4+ T, CD8+ T, and CD20+ B-cell populations were examined using flow cytometry. Results In both NECRS and ECRS patients, CD8+ T-cells were dominant over CD4+ T-cells. Notably, CD4+ T-cell/B-cell ratio, but not CD8+ T-cell/B-cell or CD4+ T-cell/CD8+ T-cell ratios, was significantly higher in ECRS patients than in NECRS patients. Conclusion The CD4+ T-cell/B-cell ratio can be used as a potential indicator to differentiate between ECRS and NECRS.

scholarly journals Single cell profiling of T and B cell repertoires following SARS-CoV-2 mRNA vaccine

2021 ◽  
Author(s):  
Suhas Sureshchandra ◽  
Sloan A. Lewis ◽  
Brianna Doratt ◽  
Allen Jankeel ◽  
Izabela Ibraim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Natural Infection ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Responses

mRNA based vaccines for SARS-CoV-2 have shown exceptional clinical efficacy providing robust protection against severe disease. However, our understanding of transcriptional and repertoire changes following full vaccination remains incomplete. We used single-cell RNA sequencing and functional assays to compare humoral and cellular responses to two doses of mRNA vaccine with responses observed in convalescent individuals with asymptomatic disease. Our analyses revealed enrichment of spike-specific B cells, activated CD4 T cells, and robust antigen-specific polyfunctional CD4 T cell responses in all vaccinees. On the other hand, CD8 T cell responses were both weak and variable. Interestingly, clonally expanded CD8 T cells were observed in every vaccinee, as observed following natural infection. TCR gene usage, however, was variable, reflecting the diversity of repertoires and MHC polymorphism in the human population. Natural infection induced expansion of larger CD8 T cell clones occupied distinct clusters, likely due to the recognition of a broader set of viral epitopes presented by the virus not seen in the mRNA vaccine. Our study highlights a coordinated adaptive immune response where early CD4 T cell responses facilitate the development of the B cell response and substantial expansion of effector CD8 T cells, together capable of contributing to future recall responses.

T Cell Recognition of HCMV: Pan-Genome Analysis of Immunogenic Open-Reading Frames.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 606-606 ◽  
Author(s):  
Louis J. Picker ◽  
Andrew W. Sylwester ◽  
Bridget L. Mitchell ◽  
Cara Taormina ◽  
Christian Pelte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cell Response ◽  
Cd8 T Cell ◽  
Cross Reactivity ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Responses

Abstract Human Cytomegalovirus (HCMV) is among the largest and most complex of known viruses with 150–200nm virions enclosing a double stranded 230kb DNA genome capable of coding for >200 proteins. HCMV infection is life-long, and for the vast majority of immune competent individuals clinically benign. Disease occurs almost exclusively in the setting of immune deficiency, suggesting that the stable host-parasite relationship that characterizes these infections is the result of an evolutionarily “negotiated” balance between viral mechanisms of pathogenesis and the host immune response. In keeping with, and perhaps because of this balance, the human CD4+ T cell response to whole HCMV viral lysates is enormous, with median peripheral blood frequencies of HCMV-specific cells ~5–10 fold higher than for analogous preparations of other common viruses. Although certain HCMV ORFs have been identified as targets of either the CD4+ or CD8+ T cell response, the specificities comprising the CD4+ T cell response, and both the total frequencies and component parts of the CD8+ T cell response are unknown. Here, we used cytokine flow cytometry and ~14,000 overlapping 15mer peptides comprising all 213 HCMV ORFs encoding proteins >100 amino acids in length to precisely define the total CD4+ and CD8+ HCMV-specific T cell responses and the HCMV ORFs responsible for these responses in 33 HCMV-seropositive, HLA-disparate donors. An additional 9 HCMV seronegative donors were similarly examined to define the extent to which non-HCMV responses cross-react with HCMV-encoded epitopes. We found that when totaled, the median frequencies of HCMV-specific CD4+ and CD8+ T cells in the peripheral blood of the seropositive subjects were 4.0% and 4.5% for the total CD4+ or CD8+ T cell populations, respectively (which corresponds to 9.1% and 10.5% of the memory populations, respectively). The HCMV-specific CD4+ and CD8+ T cell responses included a median 12 and 7 different ORFs, respectively, and all told, 73 HCMV ORFs were identified as targets for both CD4+ and CD8+ T cells, 26 ORFs as targets for CD8+ T cells alone, and 43 ORFS as targets for CD4+ T cells alone. UL55, UL83, UL86, UL99, and UL122 were the HCMV ORFs most commonly recognized by CD4+ T cells; UL123, UL83, UL48, UL122 and UL28 were the HCMV ORFs most commonly recognized by CD8+ T cells. The relationship between immunogenicity and 1) HLA haplotype and 2) ORF expression and function will be discussed. HCMV-seronegative individuals were non-reactive with the vast majority of HCMV peptides. Only 7 potentially cross-reactive responses were identified (all by CD8+ T cells) to 3 ORFs (US32, US29 and UL116) out of a total of almost 4,000 potential responses, suggesting fortuitous cross-reactivity with HCMV epitopes is uncommon. These data provide the first glimpse of the total human T cell response to a complex infectious agent, and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.

scholarly journals Comprehensive Analysis of Cell Population Dynamics and Related Core Genes During Vitiligo Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Jingzhan Zhang ◽  
Shirong Yu ◽  
Wen Hu ◽  
Man Wang ◽  
Dilinuer Abudoureyimu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Healthy Controls ◽  
Cell Abundance

Vitiligo is a common immune-related depigmentation condition, and its pathogenesis remains unclear. This study used a combination of bioinformatics methods and expression analysis techniques to explore the relationship between immune cell infiltration and gene expression in vitiligo. Previously reported gene expression microarray data from the skin (GSE53146 and GSE75819) and peripheral blood (GSE80009 and GSE90880) of vitiligo patients and healthy controls was used in the analysis. R software was used to filter the differentially expressed genes (DEGs) in each dataset, and the KOBAS 2.0 server was used to perform functional enrichment analysis. Compared with healthy controls, the upregulated genes in skin lesions and peripheral blood leukocytes of vitiligo patents were highly enriched in immune response pathways and inflammatory response signaling pathways. Immunedeconv software and the EPIC method were used to analyze the expression levels of marker genes to obtain the immune cell population in the samples. In the lesional skin of vitiligo patients, the proportions of macrophages, B cells and NK cells were increased compared with healthy controls. In the peripheral blood of vitiligo patients, CD8+ T cells and macrophages were significantly increased. A coexpression analysis of the cell populations and DEGs showed that differentially expressed immune and inflammation response genes had a strong positive correlation with macrophages. The TLR4 receptor pathway, interferon gamma-mediated signaling pathway and lipopolysaccharide-related pathway were positively correlated with CD4+ T cells. Regarding immune response-related genes, the overexpression of IFITM2, TNFSF10, GZMA, ADAMDEC1, NCF2, ADAR, SIGLEC16, and WIPF2 were related to macrophage abundance, while the overexpression of ICOS, GPR183, RGS1, ILF2 and CD28 were related to CD4+ T cell abundance. GZMA and CXCL10 expression were associated with CD8+ T cell abundance. Regarding inflammatory response-related genes, the overexpression of CEBPB, ADAM8, CXCR3, and TNIP3 promoted macrophage infiltration. Only ADORA1 expression was associated with CD4+ T cell infiltration. ADAM8 and CXCL10 expression were associated with CD8+ T cell abundance. The overexpression of CCL18, CXCL10, FOS, NLRC4, LY96, HCK, MYD88, and KLRG1, which are related to inflammation and immune responses, were associated with macrophage abundance. We also found that immune cells infiltration in vitiligo was associated with antigen presentation-related genes expression. The genes and pathways identified in this study may point to new directions for vitiligo treatment.

scholarly journals CLL Increases the Frequency of CD4+HLADR+PD1+ T Cells That Demonstrate an Exhaustion Gene Signature and Potential Prognostic Value for Disease Progression

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3033-3033
Author(s):  
Peter M Henley ◽  
Christopher Fegan ◽  
Stephen Man
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Healthy Controls ◽  
Cell Ratio ◽  
Cell Pool ◽  
Hla Dr ◽  
Healthy Donors

Alongside the expansion of leukaemic B cells, a common feature across chronic lymphocytic leukaemia (CLL) patients is widespread dysfunction in the T cell compartment. Such dysfunction can include failure to form competent immune synapses and a skewing of the T cell pool towards highly-differentiated memory cells. Previous work from our group has also demonstrated an inversion of the normal CD4+:CD8+ T cell ratio (such that CD8+ cells outnumber their CD4+ counterparts) in around a third of patients, correlating with a poor prognosis. In addition, we have defined a previously unreported CD4+ T cell subset, co-expressing HLA-DR and PD1, which occurred at higher frequencies in CLL patients compared to healthy controls and was associated with reduced progression-free survival. In this study, a new larger cohort of over 190 untreated CLL patients has been investigated. The frequency of CD4+HLA-DR+PD1+ T cells was confirmed to be greater in CLL patients (range 0.2 - 42.4%) compared to age-matched healthy donors (range 0.6 - 5.6%), while CLL patients with an inverted CD4+:CD8+ ratio had higher frequencies than those with a normal ratio. The nature and function of CD4+HLA-DR+PD1+ T cells was unknown, so phenotypic studies using multiparametric flow cytometry were undertaken. The CD4+HLA-DR+PD1+ T cell population was enriched for actively proliferative (Ki67+) and cytotoxic (Granzyme B+) cells compared to the total CD4+ T cell pool in CLL and showed no signs of cellular senescence (based on CD27 and CD28 expression). The overall patterns of co-expression of 7 phenotypic markers on CD4+HLA-DR+PD1+ T cells were highly complex and significantly different in CLL compared to age-matched healthy controls. A gene expression analysis using Human Gene 2.0 ST Arrays was conducted with FACS-sorted T cells from 5 CLL patients and 4 age-matched healthy donors, sorted into CD4+HLA-DR-PD1-, CD4+HLA-DR-PD1+ and CD4+HLA-DR+PD1+ populations. CD4+HLA-DR+PD1+ T cells showed enrichment of genes related to T cell exhaustion including TOX, recently reported as critical to exhaustion in CD8+ T cells (Alfei et al. 2019; Khan et al. 2019). Comparison of the 3 sorted T cell populations between CLL and healthy donors demonstrated enhanced expression of pathways related to cellular aging and protein turnover in CLL, as well as changes in metabolism. Longitudinal follow-up of CLL patients using data collected over periods of up to 9 years revealed that the CD4+:CD8+ T cell ratio, particularly in those with an inverted ratio, was often highly stable. By contrast, the frequency of CD4+HLA-DR+PD1+ T cells was more dynamic, with changes >2 fold observed in the course of just a few weeks in some cases. Interestingly, there was no obvious change to the patterns of CD4+HLA-DR+PD1+ T cell frequency following treatment with ibrutinib over periods of up to 10 months, with these cells remaining a dynamically changing subset during therapy. Overall, this work has shown that the CD4+HLA-DR+PD1+ T cell subset consists of a phenotypically heterogeneous population of T cells expressing genes associated with exhaustion but not senescence. The exact function of these T cells remains unclear, but CD4+HLA-DR+PD1+ T cells may represent a useful non-tumour biomarker for patients with increased risk of disease progression. This study also demonstrates the global impact of CLL on CD4+ T cells, with an effect of premature aging and altered metabolic processes. This may have important implications in the context of CLL for modern therapies which rely on the expansions of T cells, in particular chimeric antigen receptor (CAR) T cell therapy. Disclosures Fegan: Abbvie: Consultancy, Other: Conference attendance sponsorship; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria.

scholarly journals Effect of Lactobacillus plantarum IS-10506 on blood lipopolysaccharide level and immune response in HIV-infected children

2019 ◽  
Author(s):  
Alpha Fardah Athiyyah ◽  
Herwina Brahmantya ◽  
Stephani Dwiastuti ◽  
Andy Darma ◽  
Dwiyanti Puspitasari ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Count ◽  
Lactobacillus Plantarum ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Controlled Study ◽  
Probiotic Group ◽  
Cell Ratio ◽  
Cd4 T Cell Count

Background and Objectives: HIV enteropathy may cause disruption of the intestinal barrier, leading to a loss of CD4+ T cells, increased intestinal permeability, and microbial translocation. Lactobacillus plantarum IS-10506 has the ability to improve gut barrier function. This study investigated the effect of L. plantarum IS-10506 on a number of biomarkers of en- teropathy-related damage in HIV-infected paediatric patients undergoing antiretroviral therapy (ARV). Materials and Methods: A randomized, double-blind, placebo-controlled study was conducted on 2-18 year-old children, diagnosed as HIV infected according to the WHO 2007 criteria who had received ARV for ≥ 6 months. Subjects were exclud- ed if ARV therapy was discontinued or the patients took probiotics ≥ 2 weeks prior to the study or during the study period. Subjects were randomized into a probiotic group and placebo group. The probiotic group received L. plantarum IS-10506 2.86 × 1010  cfu/day for 6 days. Blood lipopolysaccharide (LPS) level, serum CD4+ T cell count, serum CD8+ T cell count, CD4+/CD8+ T cell ratio, and faecal sIgA level were assessed as biomarkers. Results: Twenty-one subjects completed this study. The blood LPS level decreased significantly in the probiotic group (p = 0.001). There was no significant difference in absolute CD4+ T cell count, percent CD4+ cells, absolute CD8+ T cell count, CD4+/CD8+ T cell ratio, or faecal sIgA. No serious adverse events were reported. Conclusion: The probiotic L. plantarum IS-10506 reduced the blood LPS level but showed no effect on the humoral mucosa and systemic immune response in HIV-infected children undergoing ARV therapy.

scholarly journals Functional expression of B7/BB1 on activated T lymphocytes.

1993 ◽  
Vol 177 (3) ◽  
pp. 845-850 ◽  
Author(s):  
M Azuma ◽  
H Yssel ◽  
J H Phillips ◽  
H Spits ◽  
L L Lanier
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Activated T Cells ◽  
T Cell Clones ◽  
Cell Clones

B7/BB1 is a membrane differentiation antigen expressed on activated B cells, macrophages, and dendritic cells that binds to a counter-receptor, CD28, expressed on T lymphocytes and thymocytes. Interaction between CD28 and B7 results in potent costimulation of T cell activation initiated via the CD3/T cell receptor complex. We now report that B7 is also expressed on activated human peripheral blood T cells, CD4 T cell clones, CD8 T cell clones, and natural killer cell clones. B7 appears relatively late after T cell activation, can be detected on both CD4 and CD8 T cell subsets, and is present on antigen-specific, major histocompatibility complex-restricted CD4 and CD8 T cell clones. Expression of B7 on activated T cells was confirmed by immunoprecipitation from 125I-labeled activated T cells and by detection of B7 transcripts. A B7+ CD4+ T cell clone was able to stimulate a primary allogeneic mixed lymphocyte response using small, resting peripheral blood T cells as responders. The alloantigen-induced proliferative response and cytokine production was partially inhibited by anti-B7 monoclonal antibody. Since activated T cells can coexpress both CD28 and its counter-receptor, B7, this suggests that activated T cells may be capable of autocrine costimulation via the CD28 activation pathway.

Longitudinal analysis of dynamic changes of T-lymphocytes during multimodal treatment of patients with inoperable stage III NSCLC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20503-e20503
Author(s):  
Thomas Philipp Hofer ◽  
Lukas Käsmann ◽  
Carolyn Pelikan ◽  
Saloni Mathur ◽  
Chukwuka Eze ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Count ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Multimodal Treatment ◽  
Stage Iii ◽  
Dynamic Changes ◽  
Stage Iii Nsclc

e20503 Background: Acute lymphocytopenia is associated with poor survival in solid cancers treated with multimodal therapy. A prospective analysis of peripheral blood mononuclear cells (PBMCs) during multimodal treatment in inoperable stage III NSCLC patients was performed to assess a correlation of T-lymphocytes changes with 6-months progression-free survival rates (PFS6M). Methods: Twenty patients at median age of 65.5 years (range 33-77), 85% male, 55% with adenocarcinoma and 40% with squamous cell carcinoma, were prospectively enrolled in this study. Eighteen (90%) patients received platinum-based concurrent chemo-radiotherapy (cCRT); seven (35%) patients additional concurrent and/or sequential immune check-point inhibition (four patients nivolumab and three durvalumab); patients treated with nivolumab received induction chemotherapy. Thoracic irradiation (TRT) was applied in all patients with median cumulative dose in equivalent 2Gy fractions (EQD2) of 64Gy (range: 52-65Gy). Peripheral blood was collected 5-10 days before treatment begin (A1), on the last day of TRT (RTend), and during follow-up. Samples were analyzed using polychromatic flow cytometry. Results are reported for three time-points: A1, RTend, and 6 months after TRT (C3) or the last sample available before that time-point. Results: From A1 to RTend, 16 (80%) patients experienced severe T-cell (CD3+, CD3+CD4+, CD3+CD8+) depletion, including 3 (15%) patients who received two doses of concurrent nivolumab. T-lymphocyte nadir was independent of the absolute numbers of PBMCs before treatment begin. In two patients, T-cell count remained stable, and increased in two other patients. No correlation of dynamic changes from A1 to RTend with PFS6M was observed. From RTend to C3, T-lymphocytes recovered in 11 (55%) patients; in 6 (30%) T-cell count further decreased or remained at very low levels. For total CD3 T-cells, CD3+CD4+ and CD3+CD8+ subsets, progressive disease in the first six months after TRT was associated with a decrease of median values (P = 0.03 for total CD3+ and CD3+CD4+, P = 0.08 for CD3+CD8+ T-cells). In contrast, an increase of all medians was associated with PFS6M (P = 0.007 for total CD3+, P = 0.002 for CD3+CD4+, P = 0.06 for CD3+CD8+ T-cells). Conclusions: There is a significant difference between patients with regards to T-lymphocytes recovery after the end of TRT, which is predictive for PFS6M, with poor median recovery observed in patients with early progress.

scholarly journals An Optimized CD4 T-Cell Response Can Control Productive and Latent Gammaherpesvirus Infection

2004 ◽  
Vol 78 (13) ◽  
pp. 6827-6835 ◽  
Author(s):  
Rebecca L. Sparks-Thissen ◽  
Douglas C. Braaten ◽  
Scott Kreher ◽  
Samuel H. Speck ◽  
Herbert W. Virgin
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Acute Infection ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cd4 T Cell

ABSTRACT CD4 T cells are important for control of infection with murine gammaherpesvirus 68 (γHV68), but it is not known whether CD4 T cells function via provision of help to other lymphocyte subsets, such as B cells and CD8 T cells, or have an independent antiviral function. Moreover, under conditions of natural infection, the CD4 T-cell response is not sufficient to eliminate infection. To determine the functional capacities of CD4 T cells under optimal or near-optimal conditions and to determine whether CD4 T cells can control γHV68 infection in the absence of CD8 T cells or B cells, we studied the effect of ovalbumin (OVA)-specific CD4 T cells on infection with a recombinant γHV68 that expresses OVA. OVA-specific CD4 T cells limited acute γHV68 replication and prolonged the life of infected T-cell receptor-transgenic RAG (DO.11.10/RAG) mice, demonstrating CD4 T-cell antiviral activity, independent of CD8 T cells and B cells. Despite CD4 T-cell-mediated control of acute infection, latent infection was established in DO.11.10/RAG mice. However, OVA-specific CD4 T cells reduced the frequency of latently infected cells both early (16 days postinfection) and late (42 days postinfection) after infection of mice containing CD8 T cells and B cells (DO.11.10 mice). These results show that OVA-specific CD4 T cells have B-cell and CD8 T-cell-independent antiviral functions in the control of acute infection and can, in the absence of preexisting CD8 T-cell or B-cell immunity, inhibit the establishment of gammaherpesvirus latency.

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