T-lymphocyte responses to the human telomerase reverse transcriptase (hTERT) in patients (pts) with advanced non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3061-3061
Author(s):  
E. Fabre ◽  
J. Medioni ◽  
M. Dosset ◽  
M. Dosset ◽  
E. Tartour ◽  
...  
Keyword(s):  
Immune Response ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Smoking Status ◽  
Performance Status ◽  
Univariate Analysis ◽  
Therapeutic Vaccine ◽  
Stage Iii ◽  
Human Telomerase Reverse Transcriptase ◽  
Lymphocyte Responses

3061 Background: hTERT is a potential target for cancer immunotherapy because it is highly expressed in tumor cells. To assess the applicability of hTERT-based immunotherapy in NSCLC, we aimed to analyse the natural anti-hTERT T-lymphocyte responses in advanced NSCLC pts. Methods: We included in a prospective, monocentric study chemonaive NSCLC pts. Pts were required to present stage III or IV tumor, without any immune deficiency or immunosuppressive drug. Before start of chemotherapy, the anti-hTERT T-lymphocyte responses were assessed in whole blood by ELISPOT and thymidine proliferation test. We evaluated the presence or absence of hTERT-specific T lymphocytes. Thereafter, we analyzed its link with age (< 60 vs. ≥ 60 yrs), ECOG performance status PS (0–1 vs. 2–3), tumoral stage (III vs. IV), histological subtype (adenocarcinoma vs. other), and smoking status (never smoker vs. smoker). Statistical analysis was performed using chi-square or Fischer test. Results: Between February and September 2008, 31 NSCLC pts were included. They presented a stage III (n = 6) or IV (n = 27) disease. Median age was 65 yrs (33–89). Eighteen pts presented anti-hTERT T lymphocytes (54%); among them we found 12 pts ≥ 60 yrs (70%), 14 adenocarcinoma (77%), 13 stage IV (72%), 7 pts with PS 2/3 (41%), and 13 smokers (72%). So far, univariate analysis showed no relationship between presence of anti-hTERT T-cell responses and pts’ characteristics. Conclusions: These preliminary results demonstrate that natural anti-hTERT immune response exists in NSCLC pts, even in case of poor prognosis. Thus, clinical trial using telomerase-based therapeutic vaccine may include NSCLC pts with advanced disease. The study is ongoing to evaluate if baseline anti-hTERT immune response could be used as selection criteria for telomerase vaccination in NSCLC. No significant financial relationships to disclose.

scholarly journals Preclinical study of a novel therapeutic vaccine for recurrent respiratory papillomatosis

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Maxwell Y. Lee ◽  
Simon Metenou ◽  
Douglas E. Brough ◽  
Helen Sabzevari ◽  
Ke Bai ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
T Lymphocyte ◽  
Chronic Infection ◽  
Therapeutic Vaccine ◽  
Preclinical Study ◽  
Recurrent Respiratory Papillomatosis ◽  
Growth Delay ◽  
Lymphocyte Responses

AbstractActivation of antigen-specific T-lymphocyte responses may be needed to cure disorders caused by chronic infection with low-risk human papillomavirus (lrHPV). Safe and effective adjuvant therapies for such disorders are needed. The safety and efficacy of a novel gorilla adenovirus vaccine expressing a protein designed to elicit immune responses directed against HPV6 and HPV11, PRGN-2012, was studied using in vitro stimulation of T lymphocytes from patients with recurrent respiratory papillomatosis, in vivo vaccination studies, and therapeutic studies in mice bearing tumors expressing lrHPV antigen. PRGN-2012 treatment induces lrHPV antigen-specific responses in patient T lymphocytes. Vaccination of wild-type mice induces E6-specific T-lymphocyte responses without toxicity. In vivo therapeutic vaccination of mice bearing established HPV6 E6 expressing tumors results in HPV6 E6-specific CD8+ T-lymphocyte immunity of sufficient magnitude to induce tumor growth delay. The clinical study of PRGN-2012 in patients with disorders caused by chronic infection with lrHPV is warranted.

scholarly journals Distinctive localization of antigen-presenting cells in human lymph nodes

Blood ◽  
2009 ◽  
Vol 113 (6) ◽  
pp. 1257-1267 ◽  
Author(s):  
Catherine E. Angel ◽  
Chun-Jen J. Chen ◽  
Oliver C. Horlacher ◽  
Sintia Winkler ◽  
Thomas John ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Lymphocytes ◽  
Lymph Nodes ◽  
T Lymphocyte ◽  
Close Contact ◽  
Antigen Presenting Cells ◽  
Lymphocyte Responses ◽  
Antigen Presenting ◽  
Medullary Cords

Abstract Professional antigen-presenting cells (APCs) are sentinel cells of the immune system that present antigen to T lymphocytes and mediate an appropriate immune response. It is therefore surprising that knowledge of the professional APCs in human lymph nodes is limited. Using 3-color immunohistochemistry, we have identified APCs in human lymph nodes, excluding plasmacytoid APCs, that fall into 2 nonoverlapping classes: (1) CD209+ APCs, coexpressing combinations of CD206, CD14, and CD68, that occupied the medullary cords, lined the capsule and trabeculae and were also scattered throughout the diffuse T-lymphocyte areas of the paracortex; and (2) APCs expressing combinations of CD1a, CD207, and CD208, that were always restricted to the paracortex. Surprisingly, this second class of APCs was almost entirely absent from many lymph nodes. Our data suggest that most CD208+ cells, often referred to as “interdigitating cells,” derive from migratory APCs, and that the major APC subset consistently resident in the paracortex of human lymph nodes is the CD209+ subset. All APC subsets were demonstrated to be in close contact with the fibroreticular network. The identification of 2 distinct APC populations in the paracortex of human lymph nodes has important implications for understanding T-lymphocyte responses and optimizing vaccine design.

scholarly journals CD4+ T Lymphocytes from Calves Immunized withAnaplasma marginale Major Surface Protein 1 (MSP1), a Heteromeric Complex of MSP1a and MSP1b, Preferentially Recognize the MSP1a Carboxyl Terminus That Is Conserved among Strains

2001 ◽  
Vol 69 (11) ◽  
pp. 6853-6862 ◽  
Author(s):  
Wendy C. Brown ◽  
Guy H. Palmer ◽  
Harris A. Lewin ◽  
Travis C. McGuire
Keyword(s):  
T Lymphocytes ◽  
T Lymphocyte ◽  
Protective Immunity ◽  
B Lymphocyte ◽  
Surface Protein ◽  
Specific Response ◽  
Major Surface Protein ◽  
Ifn Γ ◽  
Major Surface ◽  
Lymphocyte Responses

ABSTRACT Native major surface protein 1 (MSP1) of the ehrlichial pathogenAnaplasma marginale induces protective immunity in calves challenged with homologous and heterologous strains. MSP1 is a heteromeric complex of a single MSP1a protein covalently associated with MSP1b polypeptides, of which at least two (designated MSP1F1 and MSP1F3) in the Florida strain are expressed. Immunization with recombinant MSP1a and MSP1b alone or in combination fails to provide protection. The protective immunity in calves immunized with native MSP1 is associated with the development of opsonizing and neutralizing antibodies, but CD4+ T-lymphocyte responses have not been evaluated. CD4+ T lymphocytes participate in protective immunity to ehrlichial pathogens through production of gamma interferon (IFN-γ), which promotes switching to high-affinity immunoglobulin G (IgG) and activation of phagocytic cells to produce nitric oxide. Thus, an effective vaccine for A. marginaleand related organisms should contain both T- and B-lymphocyte epitopes that induce a strong memory response that can be recalled upon challenge with homologous and heterologous strains. This study was designed to determine the relative contributions of MSP1a and MSP1b proteins, which contain both variant and conserved amino acid sequences, in stimulating memory CD4+ T-lymphocyte responses in calves immunized with native MSP1. Peripheral blood mononuclear cells and CD4+ T-cell lines from MSP1-immunized calves proliferated vigorously in response to the immunizing strain (Florida) and heterologous strains of A. marginale. The conserved MSP1-specific response was preferentially directed to the carboxyl-terminal region of MSP1a, which stimulated high levels of IFN-γ production by CD4+ T cells. In contrast, there was either weak or no recognition of MSP1b proteins. Paradoxically, all calves developed high titers of IgG antibodies to both MSP1a and MSP1b polypeptides. These findings suggest that in calves immunized with MSP1 heteromeric complex, MSP1a-specific T lymphocytes may provide help to MSP1b-specific B lymphocytes. The data provide a basis for determining whether selected MSP1a CD4+ T-lymphocyte epitopes and selected MSP1a and MSP1b B-lymphocyte epitopes presented on the same molecule can stimulate a protective immune response.

scholarly journals Differential CD4+ T-Lymphocyte Apoptosis and Bystander T-Cell Activation in Rhesus Macaques and Sooty Mangabeys during Acute Simian Immunodeficiency Virus Infection

2008 ◽  
Vol 83 (2) ◽  
pp. 572-583 ◽  
Author(s):  
Mareike Meythaler ◽  
Amanda Martinot ◽  
Zichun Wang ◽  
Sarah Pryputniewicz ◽  
Melissa Kasheta ◽  
...  
Keyword(s):  
Immune Response ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Immune Activation ◽  
Rhesus Macaques ◽  
Lymphocyte Apoptosis ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys ◽  
Siv Infection ◽  
Species Specific

ABSTRACT In contrast to pathogenic lentiviral infections, chronic simian immunodeficiency virus (SIV) infection in its natural host is characterized by a lack of increased immune activation and apoptosis. To determine whether these differences are species specific and predicted by the early host response to SIV in primary infection, we longitudinally examined T-lymphocyte apoptosis, immune activation, and the SIV-specific cellular immune response in experimentally infected rhesus macaques (RM) and sooty mangabeys (SM) with controlled or uncontrolled SIV infection. SIVsmE041, a primary SIVsm isolate, reproduced set-point viremia levels of natural SIV infection in SM but was controlled in RM, while SIVmac239 replicated to high levels in RM. Following SIV infection, increased CD8+ T-lymphocyte apoptosis, temporally coinciding with onset of SIV-specific cellular immunity, and elevated plasma Th1 cytokine and gamma interferon-induced chemokine levels were common to both SM and RM. Different from SM, SIV-infected RM showed a significantly higher frequency of peripheral blood activated CD8+ T lymphocytes despite comparable magnitude of the SIV-specific gamma interferon enzyme-linked immunospot response. Furthermore, an increase in CD4+ and CD4−CD8− T-lymphocyte apoptosis and plasma tumor necrosis factor-related apoptosis-inducing ligand were observed only in RM and occurred in both controlled SIVsmE041 and uncontrolled SIVmac239 infection. These data suggest that the “excess” activated T lymphocytes in RM soon after SIV infection are predominantly of non-virus-specific bystander origin. Thus, species-specific differences in the early innate immune response appear to be an important factor contributing to differential immune activation in natural and nonnatural hosts of SIV infection.

Impact of ECOG performance status on recurrent/metastatic head and neck squamous cell carcinomas treated with anti-PD1 inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18004-e18004
Author(s):  
Cameron Chalker ◽  
Vicky Wu ◽  
Jenna M. Voutsinas ◽  
Victoria Hwang ◽  
Christina S Baik ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Outcomes ◽  
Squamous Cell ◽  
Smoking Status ◽  
Demographic Data ◽  
Performance Status ◽  
Univariate Analysis ◽  
Single Agent ◽  
Ecog Performance Status ◽  
Hpv Status

e18004 Background: Anti-PD1 checkpoint inhibitors (ICI) represent an established standard of care for patients with recurrent/metastatic head & neck squamous cell carcinoma (RMHNSCC). Landmark studies excluded patients with ECOG performance status (PS) ≥ 2; the benefit of ICI in this population is therefore unknown. Methods: We retrospectively reviewed RMHNSCC patients who received at least 1 dose of ICI at our institution. Demographic data and clinical outcomes were obtained; the latter included objective response to ICI (ORR), physician-documented CTCAE grade 2+ toxicity (irAE), and any unplanned hospitalization within 100-days of last ICI dose (UH). Associations between demographic data and clinical outcomes were explored using both uni- and multivariate analysis. Overall survival (OS) was estimated using a Cox proportional hazards model; ORR, irAE, and UH were evaluated with logistic regression. This project was approved by our institutional IRB. Results: We identified 152 RMHNSCC patients who were treated with ICI between 1/2013 and 1/2019. ECOG PS was 0 in 42 (27%), 1 in 75 (50%), 2 in 27 (18%), 3 in 2 (1%), and unknown in 6 (4%) patients. The median age was 61 (range: 25 - 90). 124 (82%) were male, 124 (82%) were white, and 69 (45%) were never-smokers. The most common primary sites were the oropharynx (n = 59, 40%), oral cavity (n = 39, 26%), nasopharynx (n = 11, 7%), and larynx (n = 10, 6%). 54 (36%) were p16+ oropharynx cancers. CPS score was available in 10 (6.6%). Single agent ICI was received by 118 (77%) patients. 66 (44%) had a documented irAE and 54 (36%) had an UH. A multivariate model for OS containing PS, smoking status and HPV status showed a strong association between inferior OS and ECOG 2/3 compared to 0/1 (p < 0.001; HR = 3.30, CI = 2.01-5.41), as well as former (vs. never) smoking status (p < 0.001; HR = 2.17, CI = 1.41-3.35). Current smoking (p = 0.25) did not reach statistical significance. On univariate analysis, poor PS was associated with inferior ORR (p = 0.03; OR = 0.25, CI = 0.06-0.77) and increased UH (p = 0.04; OR = 2.43, CI = 1.05—5.71). There was no significant association between irAE and any patient characteristic. Conclusions: We observed inferior overall survival among ICI-treated RMHNSCC patients with ECOG 2/3 in our single-institution, retrospective series. Our findings help frame discussion of therapeutic options in this poor-risk population. Further study must be done to determine which interventions are of greatest benefit for RMHNSCC patients with declining performance status.

scholarly journals Immune Checkpoint Receptors Tim-3 and PD-1 Regulate Monocyte and T Lymphocyte Function in Septic Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Qi Xia ◽  
Li Wei ◽  
Yuntao Zhang ◽  
Jifang Sheng ◽  
Wei Wu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
T Lymphocytes ◽  
Signaling Pathway ◽  
T Lymphocyte ◽  
Receptor Blockade ◽  
Lymphocyte Function ◽  
Significant Elevation ◽  
Programmed Cell Death 1 ◽  
Checkpoint Receptors

We aim to investigate the effects of Tim-3 and programmed cell death-1 (PD-1) on the monocytes and T lymphocytes in septic patients. Expression of Tim-3 and PD-1 on the CD3, CD4, and CD8 lymphocytes and monocytes was determined using flow cytometry. CBA technique was utilized to determine the expression of cytokines in the lymphocyte supernatant in addition to the IL-10 and TNF-αpositivity in monocytes in the presence of Tim-3 and/or PD-1 receptor blockade. Compared with the normal control, significant elevation was observed in the expression of PD-1 on CD3 (P=0.004), CD4, and CD8 monocytes. Blockade of the Tim-3 signaling pathway contributed to the significant elevation of IL-10 and TNF-αin the supernatant of T lymphocytes in the septic patients, while the PD-1 signaling pathway blockade only triggered the obvious elevation of TNF-αin the T lymphocytes. Blockade of Tim-3 and PD-1 induced the positivity of IL-10- and TNF-α-expressing cells in the peripheral monocytes. Significant changes were noticed in the Tim-3 and PD-1 in the T lymphocytes and monocytes. Blockade of Tim-3 and PD-1 contributed to the function of lymphocytes and monocytes. In the septic process, Tim-3 and PD-1 played crucial roles in the immune response of T lymphocytes and monocytes.

scholarly journals Carbohydrate supplementation and exercise-induced changes in T-lymphocyte function

2003 ◽  
Vol 95 (3) ◽  
pp. 1216-1223 ◽  
Author(s):  
Katherine J. Green ◽  
Susan J. Croaker ◽  
David G. Rowbottom
Keyword(s):  
Cell Death ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Immune Cell ◽  
Ventilatory Threshold ◽  
Random Order ◽  
Cortisol Response ◽  
Lymphocyte Function ◽  
Lymphocyte Responses ◽  
Response To Exercise

Carbohydrate (CHO) ingestion during exercise has been shown to reduce perturbations in immune cell numbers and function, possibly through a reduction in the cortisol response to exercise. We have previously observed that exercise decreases T-lymphocyte responses to mitogen via an increase in cell death of both CD4 and CD8 T lymphocytes (Green KJ and Rowbottom DG. J Appl Physiol. 95: 57-63, 2003). This study tested the hypothesis that CHO ingestion rather than placebo (Pl) would result in an attenuation of the cortisol response to exercise and a reduction of the exercise-associated alterations in cell death. Six well-trained cyclists completed two exercise trials consisting of 2.5 h of cycling at 85% of individual ventilatory threshold. In a random order, trials were completed under either CHO (6% CHO solution, 3.2 g CHO/kg body wt total) or Pl conditions. Blood samples were collected before exercise, midexercise (after 60 min of exercise), immediately after exercise, and after 60 min of recovery. T-lymphocyte responses to mitogen were determined by using carboxyfluorescein diacetate succinimidyl ester fluorescent cell division tracking and expansion rates, and cell death rates were calculated for each sample as well as mitosis rates for each cell generation. Cellular expansion of T lymphocytes was decreased after exercise in Pl only. The reduction in cellular expansion was related to an increase in cell death of both CD4 and CD8 cells in culture rather than a decrease in the ability of cells to undergo mitosis. CHO ingestion compared with Pl was associated with no reductions in cellular expansion or increases in cell death. CHO ingestion during exercise acted to reduce the impairment of T-lymphocyte function by decreasing cell death within mitogen-stimulated cell cultures; however, the mechanism of action appears to be independent of cortisol.

scholarly journals FUNCTION OF MACROPHAGES IN ANTIGEN RECOGNITION BY GUINEA PIG T LYMPHOCYTES

1973 ◽  
Vol 138 (5) ◽  
pp. 1213-1229 ◽  
Author(s):  
Ethan M. Shevach ◽  
Alan S. Rosenthal
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
Binding Site ◽  
T Lymphocyte ◽  
Lymphocyte Transformation ◽  
Antigen Recognition ◽  
Histocompatibility Antigens ◽  
Recognition Sites

A number of recent studies have suggested that the main functional role of the product of the immune response (Ir) genes is in the process of antigen recognition by the T lymphocyte. The observation in the accompanying report that the interaction of macrophage-associated antigen with immune T lymphocytes requires that both cells share histocompatibility antigens raised the question as to whether the macrophage played a role in the genetic control of the immune response or even if the macrophage were the primary cell in which the product of the Ir gene is expressed. In the current study, parental macrophages were pulsed with an antigen, the response to which is controlled by an Ir gene lacking in that parent; these macrophages were then mixed with T cells derived from the (nonresponder x responder)F1 and the resultant stimulation was measured. No stimulation was seen when column-purified F1 lymph node lymphocytes were mixed with antigen-pulsed macrophages from the nonresponder parent. However, when the highly reactive peritoneal exudate lymphocyte population was used as the indicator cells, parental macrophages pulsed with an antigen whose Ir gene they lacked were capable of initiating F1 T-cell proliferation. The magnitude of stimulation was approximately 1/10 that seen when macrophages from either the responder parent or the F1 were used. In order to explain this observation, we hypothesize that antigen recognition sites on the T lymphocyte are physically related to a macrophage-binding site and both are linked to the serologically determined histocompatibility antigens. Thus, parental macrophages pulsed with an antigen, whose Ir gene they lack, activate F1 cells poorly because the recognition sites for the antigen are physically related to the macrophage-binding site of the responder parent while the main contacts between the cells are at the nonresponder binding sites. Experiments performed with alloantisera lend support to this hypothesis. Thus, when parental macrophages are pulsed with any antigen and added to F1 T cells, an alloantiserum directed against parental histocompatibility antigens reacts with both the lymphocyte and the macrophage and thereby inhibits macrophage-lymphocyte interaction and abolishes antigen-induced lymphocyte transformation. When the alloantisera are directed at determinants present solely on the T lymphocyte, they only inhibit the recognition of antigens controlled by the Ir gene linked to the histocompatibility antigen against which they are directed. We conclude from these studies that antigen recognition by the T lymphocyte is a complex multicellular event involving more than simple antigen binding to a specific lymphocyte receptor.

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