scholarly journals Notch-1 Inhibition Promotes Immune Regulation in Transplantation Via Regulatory T Cell–Dependent Mechanisms

Circulation ◽  
2019 ◽  
Vol 140 (10) ◽  
pp. 846-863 ◽  
Author(s):  
Ciara N. Magee ◽  
Naoka Murakami ◽  
Thiago J. Borges ◽  
Tetsunosuke Shimizu ◽  
Kassem Safa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Lung Transplant ◽  
Cell Mediated Immunity ◽  
Cardiac Transplant ◽  
Solid Organ ◽  
Notch 1 ◽  
Transplant Model

Background: Transplantation is the treatment of choice for many patients with end-stage organ disease. Despite advances in immunosuppression, long-term outcomes remain suboptimal, hampered by drug toxicity and immune-mediated injury, the leading cause of late graft loss. The development of therapies that promote regulation while suppressing effector immunity is imperative to improve graft survival and minimize conventional immunosuppression. Notch signaling is a highly conserved pathway pivotal to T-cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell–mediated immunity. Methods: We investigated the pattern of Notch-1 expression in effector and regulatory T cells (Tregs) in both murine and human recipients of a solid-organ transplant. Using a selective human anti-Notch-1 antibody (aNotch-1), we examined the effect of Notch-1 receptor inhibition in full major histocompatibility complex–mismatch murine cardiac and lung transplant models, and in a humanized skin transplant model. On the basis of our findings, we further used a genetic approach to investigate the effect of selective Notch-1 inhibition in Tregs. Results: We observed an increased proportion of Tregs expressing surface and intracellular (activated) Notch-1 in comparison with conventional T cells, both in mice with transplants and in the peripheral blood of patients with transplants. In the murine cardiac transplant model, peritransplant administration of aNotch-1 (days 0, 2, 4, 6, 8, and 10) significantly prolonged allograft survival in comparison with immunoglobulin G–treated controls. Similarly, aNotch-1 treatment improved both histological and functional outcomes in the murine lung transplant model. The use of aNotch-1 resulted in a reduced proportion of both splenic and intragraft conventional T cells, while increasing the proportion of Tregs. Furthermore, Tregs isolated from aNotch-1–treated mice showed enhanced suppressive function on a per-cell basis, confirmed with selective Notch-1 deletion in Tregs (Foxp3 EGFPCre Notch1 fl/fl ). Notch-1 blockade inhibited the mammalian target of rapamycin pathway and increased the phosphorylation of STAT5 (signal transducer and activator of transcription 5) in murine Tregs. Notch-1 low Tregs isolated from human peripheral blood exhibited more potent suppressive capacity than Notch-1 high Tregs. Last, the combination of aNotch-1 with costimulation blockade induced long-term tolerance in a cardiac transplant model, and this tolerance was dependent on CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4) signaling. Conclusions: Our data reveal a promising, clinically relevant approach for immune modulation in transplantation by selectively targeting Notch-1.

scholarly journals Quantitative analysis of the CD8 + T–cell response to readily eliminated and persistent viruses

2000 ◽  
Vol 355 (1400) ◽  
pp. 1093-1101 ◽  
Author(s):  
P. C. Doherty ◽  
J. M. Riberdy ◽  
G. T. Belz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Flow Cytometric Analysis ◽  
T Cell Response ◽  
Basic Question ◽  
Cell Mediated Immunity ◽  
Specific Response ◽  
Turnover Rates

The recent development of techniques for the direct staining of peptide–specific CD8 + T cells has revolutionized the analysis of cell–mediated immunity (CMI) in virus infections. This approach has been used to quantify the acute and long–term consequences of infecting laboratory mice with the readily eliminated influenza A viruses (fluA) and a persistent γherpesvirus (γHV). It is now, for the first time, possible to work with real numbers in the analysis of CD8 + T CMI, and to define various characteristics of the responding lymphocytes both by direct flow cytometric analysis and by sorting for further in vitro manipulation. Relatively little has yet been done from the latter aspect, though we are rapidly accumulating a mass of numerical data. The acute, antigen–driven phases of the fluA and γHV–specific response look rather similar, but CD8 + T–cell numbers are maintained in the long term at a higher ‘set point’ in the persistent infection. Similarly, these ‘memory’ T cells continue to divide at a much greater rate in the γHV–infected mice. New insights have also been generated on the nature of the recall response following secondary challenge in both experimental systems, and the extent of protection conferred by large numbers of virus–specific CD8 + T cells has been determined. However, there are still many parameters that have received little attention, partly because they are difficult to measure. These include the rate of antigen–specific CD8 + T–cell loss, the extent of the lymphocyte ‘diaspora’ to other tissues, and the diversity of functional characteristics, turnover rates, clonal life spans and recirculation profiles. The basic question for immunologists remains how we reconcile the extraordinary plasticity of the immune system with the mechanisms that maintain a stable milieu interieur. This new capacity to quantify CD8 + T–cell responses in readily manipulated mouse models has obvious potential for illuminating homeostatic control, particularly if the experimental approaches to the problem are designed in the context of appropriate predictive models.

scholarly journals Immunologically mediated regression of a murine lymphoma after treatment with anti-L3T4 antibody. A consequence of removing L3T4+ suppressor T cells from a host generating predominantly Lyt-2+ T cell-mediated immunity.

1988 ◽  
Vol 168 (6) ◽  
pp. 2193-2206 ◽  
Author(s):  
M Awwad ◽  
R J North
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Regression ◽  
Cell Mediated Immunity ◽  
Complete Regression ◽  
Suppressor T Cells ◽  
Antibody Treatment ◽  
P815 Mastocytoma ◽  
Thymectomized Mice

This study shows that intravenous injection of 1 mg of anti-L3T4 mAb (GK1.5) into thymectomized mice bearing the syngeneic L5178Y lymphoma results, after a delay of 2-3 d, in complete regression of this tumor and in long-term host survival. A flow cytofluorometric examination of the spleen cells of mAb-treated mice revealed that antibody treatment resulted in the elimination of greater than 98% of L3T4+ T cells, but had no effect on the Lyt-2+ T cells subset. Tumor regression was immunologically mediated, because L5178Y lymphoma cells were shown to be L3T4-, and regression of the tumor failed to occur in mice that had been lethally irradiated before anti-L3T4 mAb was given. Tumor regression was mediated by tumor-sensitized Lyt2+ T cells, as evidenced by the finding that treatment of tumor-bearing mice with anti-Lyt-2 mAb alone, or in combination with anti-L3T4 mAb, resulted in enhancement of tumor growth and a significant decrease in host survival time. Moreover, the spleens of mice whose tumors were undergoing regression in response to anti-L3T4 mAb treatment contained Lyt-2+ T cells capable, on passive transfer, of causing regression of a tumor in recipient mice. These results can be interpreted as showing that removal of tumor-induced L3T4+ suppressor T cells results in the release of Lyt-2+ effector T cells from suppression, and consequently in the generation of enough Lyt-2+ T cell-mediated immunity to cause tumor regression. This can only be achieved, however, if immunity to the tumor is mediated exclusively by Lyt-2+ T cells, as is the case for the L5178Y lymphoma. In the case of the P815 mastocytoma, treatment with anti-L3T4 mAb was without a therapeutic effect, and this was in keeping with the finding that immunity to this tumor is mediated by L3T4+, as well by Lyt-2+ T cells.

scholarly journals New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

Biomedicines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 55 ◽  
Author(s):  
Volker Schirrmacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Tumor Immunity ◽  
Cancer Vaccines ◽  
Cell Mediated Immunity ◽  
Anti Cancer ◽  
Antigen Presenting ◽  
Molecular Patterns

The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity and thus a detailed understanding of cognate interactions between tumor antigen (TA)-specific T cells and TA-presenting dendritic cells. Microbes and their associated molecular patterns initiate early inflammatory defense reactions that can contribute to the activation of antigen-presenting cells (APCs) and to costimulation of T cells. The concommitant stimulation of naive TA-specific CD4+ and CD8+ T cells with TAs and costimulatory signals occurs in T-APC clusters that generate effectors, such as cytotoxic T lymphocytes and T cell mediated immunological memory. Information about how such memory can be maintained over long times is updated. The role that the bone marrow with its specialized niches plays for the survival of memory T cells is emphasized. Examples are presented that demonstrate long-term protective anti-tumor immunity can be achieved by post-operative vaccination with autologous cancer vaccines that are modified by virus infection.

scholarly journals Peripheral T cell activation in long-term renal transplant patients: concordant upregulation of adhesion molecules and cytokine gene transcription.

1996 ◽  
Vol 7 (11) ◽  
pp. 2476-2482 ◽  
Author(s):  
F Kern ◽  
S Ode-Hakim ◽  
H Nugel ◽  
K Vogt ◽  
H D Volk ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Renal Transplant ◽  
Peripheral Blood ◽  
Cmv Infection ◽  
Cytotoxic Potential ◽  
Granzyme A ◽  
Transplant Patients ◽  
Renal Transplant Patients

In renal transplant, patients, the number of T cells expressing high levels of LFA-1 (LFA-1-bright) and of T cells expressing CD57 increases in response to viral infection, even if the latter is asymptomatic. Their role in long-term renal transplant patients with cytomegalovirus (CMV) antigenemia and concomitant transplant dysfunction was investigated. For this purpose, this study used triple-color flow cytometry, fluorescence-activated cell sorting of peripheral blood T cells (CD3+/LFA-1-dim or -bright and CD8+/CD57+ or CD57- subsets), and subsequent semiquantitative reverse transcription-polymerase chain reaction. Cytokine mRNA levels for interleukin (IL)-1 beta, IL-2, IL-4, IL-8, IL-10, tumor necrosis factor alpha, and interferon-gamma, as well as Granzyme A and IL-2R p55 and p75 transcripts were determined and compared in peripheral blood mononuclear cells and in separated T cell subsets. Although in patients with CMV infection and/or rejection, cytokine transcripts were readily detected and the levels in the CD3+/LFA-1-bright subsets were, by orders of magnitudes, higher than in the LFA-1-dim subset, hardly any cytokine message was found in patients without CMV infection or rejection episodes or in control subjects. The expression of Granzyme A, which is involved in cytotoxic T lymphocyte-mediated cytotoxicity, was not upregulated in LFA-1-bright T cells, which is in discordance with cytokine levels. Differences between CD57+ and CD57- T cells were limited to the IL-2R p55 mRNA, of which the former expressed significantly less than the latter. It is concluded that upon virus-induced activation of peripheral blood T cells, an effector type that is marked by high inflammatory but small cytotoxic potential is produced. The results of this study propose that these cells represent a correlate of persistent immune activation and are liable to produce graft dysfunction, although they are unable to clear the organism from virus infection because of their lack of cytotoxic potential.

scholarly journals Age related human T cell subset evolution and senescence

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Mingde Li ◽  
Danlin Yao ◽  
Xiangbo Zeng ◽  
Dimitri Kasakovski ◽  
Yikai Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Memory T Cells ◽  
Cell Subset ◽  
Absolute Number ◽  
T Cell Subsets ◽  
And Gender

Abstract T cells are fundamental effector cells against viruses and cancers that can be divided into different subsets based on their long-term immune protection and immediate immune response effects. The percentage and absolute number of these subsets change with ageing, which leads to a reduced immune response in older individuals. Stem cell memory T cells (TSCM) represent a small population of memory T cells with enhanced proliferation and differentiation properties that are endowed with high potential for maintaining T cell homeostasis. However, whether these cells change with ageing and gender remains unknown. Here, we assayed the distribution of TSCM and other T cell subsets in peripheral blood from 92 healthy subjects (44 females and 48 males) ranging from 3 to 88 years old by flow cytometry. We found that CD4+ and CD8+ TSCM in the circulation have relatively stable frequencies, and the absolute number of CD8+ TSCM decreased with age; however, the ratio of TSCM to the CD4+ or CD8+ naïve population increased with age. Unlike the obvious changes in other T cell subsets with age and gender, the stable level of TSCM in peripheral blood may support their capacity for sustaining long-term immunological memory, while their importance may increase together with ageing.

scholarly journals Reconstitution of T-cell-mediated immunity in patients after allogeneic stem cell transplantation

2020 ◽  
Vol 65 (1) ◽  
pp. 24-38
Author(s):  
N. N. Popova ◽  
V. G. Savchenko
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cell Mediated Immunity ◽  
Term Survival ◽  
Post Transplant

Background. The timely reconstitution of the donor-derived immune system is a key factor in the prevention of such post-transplant complications as graft versus host disease, relapse or secondary tumours and various infections. These complications affect the long-term survival of patients after allogeneic stem cell transplantation.Aim — to describe the main stages of T Cell–mediated immune recovery in patients after allogeneic stem cell transplantation.General findings. T-cell–mediated immunity is responsible for anti-infective and anti-tumour immune response. The early post-transplant period is characterized by the thymus-independent pathway of T-cell recovery largely involving proliferation of mature donor T cells, which were transplanted to the patient together with hematopoietic stem cells. To a lesser extent, this recovery pathway is realized through the expansion of host naïve and memory T cells, which survived after conditioning. Thymus-dependent reconstitution involves generation of de novo naïve T cells and subsequent formation of a pool of memory T-cells providing the main immunological effects — graft versus tumour and graft versus host reactions. A better understanding of the T-cell immune reconstitution process is important for selecting optimized pre-transplant conditioning regimens and patient-specific immunosuppressive therapy approaches, thus reducing the risks of post-transplant complications and improving the long-term survival of patients after allogeneic stem cell transplantation.

Analysis of the Recent Thymic Output Function of 23 TCR Vβ Subfamily Naïve T Cells in Patients with AML.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4482-4482
Author(s):  
Qingsong Yin ◽  
Yangqiu Li ◽  
Lijian Yang ◽  
Shaohuao Chen ◽  
Xueli Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Output Function ◽  
Recent Thymic Emigrants ◽  
Thymic Output ◽  
Normal Individuals ◽  
Tcr Repertoire ◽  
Cellular Immune

Abstract Regeneration of the T-cell population proceeds normally along two different pathways, in which the thymic-dependent pathway accounts for the more durable reconstitution of the T-cell compartment, and generates a more diverse TCR repertoire. Thus thymus function serves as a direct index to understand cellular immune function and potential of long-term TCR Vβ repertoire reconstitution. The complexity of TCR repertoire is generated in the thymus by regular recombination of series of gene fragments of TCR α or β chains. During these process, by-products of rearrangements are generated in the form of signal joint T-cell receptor excision DNA circles(sjTRECs), as sjTRECs are stable extrachromosomal annular DNA, are not replicated while cell dividing, and their existence suggests functional TCR generation. Thus thymic function can be evaluated by measuring sjTRECs in peripheral blood. At present, the total recent thymic output function is evaluated by quantitating δRec-ψJα sjTRECs, but it can not evaluate particular thymic emigrants of different Vα or Vβ subfamily naïve T cells. As TCR Vα and Vβ naïve T cells include many subfamilies which play different immune roles, and the complexity of TCR repertoire is an important factor for cellular immune reconstitution. Our previous studies had showed that the recent thymic output function in patients with AML was significant decrease by quantitative detection of δRec-ψJα sjTRECs. To further estimate the recent thymic emigrants of different TCR Vβ subfamily naïve T cells, this study was designed to detect the existence of 23 TCR Vβ subfamily sjTRECs in peripheral blood mononuclear cells (PBMCs) by using 23 Vβ subfamily special primers (including 2Dβ1 sense primers and 23 Vβ subfamily antisense primers). TCR 23 Vβ-Dβ 1 sjTRECs were separately amplified in genomic DNA from 5×104 and 1×104 PBMCs of samples (10 cases of normal individuals and 32 cases of the different FAB subtypes of AML patients) to estimate the frequencies of TCR 23 Vβ-Dβ1 sjTRECs by using semi-nest PCR. The results indicated that the frequencies of 23 Vβ-Dβ1 sjTRECs were different at the same cellular concentration, and the higher cellular concentration the higher frequency of Vβ subfamily sjTRECs. The number of detectable Vβ subfamily sjTRECs was (5.09±3.28) and (2.59±2.06) in 5×104 and 1×104 PBMCs from AML patients, as compared with (13.7±2.67) and (5.50±2.07) from normal individuals, and the differences were significant (both p=0.000). About 5/23(22%) of Vβ-Dβ1 sjTRECs were detected in 5×104 PBMCs from AML patients, and the frequencies of 13 Vβ subfamily sjTRECs (including Vβ1,Vββ,Vβ3,Vβ4,Vβ5, Vβ9,Vβ10,Vβ12,Vβ13,Vβ14,Vβ17,Vβ22,Vβ24-Dβ1 sjTRECs) were significantly lower than those from normal individuals, among which the lowest were Vβ10 and Vβ14-Dβ1 sjTRECs, the most frequency was Vβ21. But the difference was not significant within the different FAB subtypes of AML patients. It was negative correlation between age and the number of detectable Vβ subfamily sjTRECs in patients with AML, and patients who were < 30 years tended to be higher number of detectable Vβ subfamily sjTRECs than those ≥ 30 years, which became significant at 5×104 PBMCs level (r=−0.481, p=0.005). Taken together, the recent thymic emigrants of 23 Vβ subfamily naïve T cells were absent to a different extent or lower level among patients with AML. These results suggested that AML patients had severe cellular immunodeficiency and the capacity and potential of long-term TCR Vβ repertoire reconstitution were dramatically lowered.

Effect of hyperbaric oxygen on tissue distribution of mononuclear cell subsets in the rat

1994 ◽  
Vol 77 (5) ◽  
pp. 2355-2359 ◽  
Author(s):  
N. Bitterman ◽  
N. Lahat ◽  
T. Rosenwald ◽  
A. Kinarty ◽  
Y. Melamed ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hyperbaric Oxygen ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Interleukin 2 ◽  
T Cell Subsets ◽  
Cell Mediated Immunity ◽  
Lymph Glands

In a previous study we found a significant temporary decrease in the ratio of CD4/CD8 (helper, inducer/suppressor, cytotoxic) T lymphocytes in the peripheral blood of healthy human volunteers after exposure to a single commonly used profile of hyperbaric oxygen (HBO). The transient nature of the changes suggested redistribution of T-cell subsets. The purpose of the present study was to verify such a redistribution and to locate possible target organs in an animal model. A single exposure of rats to HBO (0.28 MPa) induced a highly significant rapid decrease in the CD4/CD8 ratio in peripheral blood count (P < 0.0001), confirming our previous findings in humans. HBO also induced a significant increase in the CD4/CD8 ratio in the lungs and lymph nodes (P < 0.001) and a significant decrease in the ratio in the spleen (P < 0.01). Furthermore, exposure to HBO induced a significant increase in T cells bearing surface interleukin-2 receptors in the blood, spleen, lungs, and lymph glands (P < 0.001) and a significant decrease in T cells expressing alpha beta-receptors in the lungs (P < 0.001) and lymph glands (P < 0.05). Our findings suggest rapid T-cell activation after a brief exposure to HBO, with shifts of CD4 and CD8 subsets and variations in T-cell receptor type. These rapid changes in the parameters of cell-mediated immunity may represent the activation of protective mechanisms against the toxic effect of oxygen or the early stages of pulmonary oxygen toxicity.

Phenotypically and Functionally Altered T Cell Compartment in DLBCL Patients at Diagnosis and Its Long-Term Modification upon Chemoimmunotherapy Regimen

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1529-1529 ◽  
Author(s):  
Maria Christina Cox ◽  
Simone Battella ◽  
Raffaella La Scaleia ◽  
Arianna di Napoli ◽  
Sabrina Pelliccia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Absolute Number ◽  
T Cell Subsets ◽  
Newly Diagnosed ◽  
Cell Compartment ◽  
Functional Competence ◽  
Therapy Completion

Abstract Background: Peripheral blood lymphopenia at diagnosis and after treatment has been widely reported as a negative prognostic factor in DLBCL. This phenomenon, which reflects host systemic immunity, is still poorly characterized. Very recently, we have described a profound phenotypic and functional alteration of the peripheral NK cell compartment in newly-diagnosed DLBCL patients at diagnosis and upon R-CHOP chemoimmunotherapy, and suggested that the complex dynamics of the immune system plays a pivotal role in the response to chemoimmunotherapy. Since the role of T cell-dependent memory and effector capabilities in long-term cure of chemoimmunotherapy-treated cancer patients is increasingly appreciated, we have focused our studies on their modifications in DLBCL. Aims: To analyze the phenotypic and functional profile of peripheral blood T lymphocyte compartment in DLBCL patients at diagnosis, and to assess the long-term impact of R-CHOP chemoimmunotherapy on T cell populations and functional competence. Patients and Methods: We prospectively compared 32 consecutive newly diagnosed DLBCL patients with 27 healthy, age- and sex-matched controls for: 1) absolute number (/mcl) and percentage (over PBMC) of the main T cell subsets: "conventional CD4+ and CD8+, double positive (CD4+CD8+), double negative (CD4-CD8-), CD56+ innate-like, and FOXP3+CD25bright regulatory T cells (Treg), measured by blood cell count and multi-parameter flow cytometric (FACS) analysis; 2) functional capability of T cell subsets, evaluated as the frequency of IFN gamma (IFNg)-producing cells upon a short-term (6-hr) stimulation with PMA/ionomycin, and the percentage of GrzB+ (cytotoxic granule marker) cells; and 3) plasma concentration of selected cytokines. Patients were analyzed at diagnosis, during and at different timepoints after chemoimmunotherapy completion. Results: DLBCL patients at diagnosis showed lower lymphocyte count (p<.001), mostly due to a selective decrement of CD4+ T cells (p=.003) and B lymphocytes (p=.0001). The absolute number of CD8+ or innate-like CD56+ T cells were not affected. As a result, the relative CD4/CD8 ratio was decreased (p=.009). The absolute number, but not the percentage, of Treg was slightly reduced with respect to controls. While CD8+ and innate-like T cell subsets transiently decreased during R-CHOP cycles, CD4+ T cell and Treg absolute numbers remained significantly lower than controls up to 1 year after therapy completion. As a result, CD4/CD8 ratio also remained lower than controls, up to 1 year after therapy. The phenotypically skewed T cell profile of DLBCL patients at diagnosis was associated with severe functional alterations, as the frequencies of IFNg-producing and Granzyme B-expressing cells were increased in both CD4+ (p=.007 for IFNg+ and p=.005 for GrzB+) and CD8+ (p=.002 for IFNg+ and p<.0001 for GrzB+) conventional T cell subsets. Noteworthy, the functional competence of innate-like CD56+ T cells showed no difference with controls. The frequency of GrzB+ and IFNg-producing CD4+ and CD8+ T cells transiently decreased during therapy, thus becoming comparable to controls, raised again by three months after therapy, and was persistingly higher than controls up to 1 year after therapy completion. Finally, IL-6 and IL-10 plasma levels were significantly elevated in DLBCL at diagnosis (p<.0001 and p=.011, respectively), and gradually normalized, shortly after R-CHOP therapy completion. Interestingly, CD4+ and CD8+ T cell capability to promptly produce IFNg was significantly higher in GC, but not in non-GC DLBCL patients at diagnosis, suggesting that patients T cell functional features may depend on DLBCL phenotype. Moreover, a higher percentage of IFNg+ T cells was observed in patients attaining a long-term remission, but not in resistant or relapsing ones, hinting to the association of immune competence with therapy outcome. Conclusions: T cell-dependent memory and effector capabilities might significantly contribute to the success of chemoimmunotherapy strategies, as suggested by the recently discovered vaccinal effect. The novel information provided by this study may reveal useful for innovative therapeutic approaches more focused on exploiting the dynamics of host immune cells in fighting cancer. *MC Cox and S Battella contributed equally to this work Disclosures No relevant conflicts of interest to declare.

scholarly journals Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up

2020 ◽  
Vol 8 (2) ◽  
pp. e000848 ◽  
Author(s):  
Joost H van den Berg ◽  
Bianca Heemskerk ◽  
Nienke van Rooij ◽  
Raquel Gomez-Eerland ◽  
Samira Michels ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Metastatic Melanoma ◽  
Peripheral Blood ◽  
Tumor Infiltrating Lymphocytes ◽  
Phase Iii ◽  
Cell Reactivity ◽  
T Cell Reactivity ◽  
Infiltrating Lymphocytes

Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50% of treated patients, have been observed across hospitals, including a substantial fraction of durable, complete responses.PurposeExecute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial.ExperimentalTen patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products.ResultsFive out of 10 patients, who were all anti-PD-1 naïve at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion.ConclusionThe clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial.

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