scholarly journals Targeting PD-L1 and TIGIT Could Restore Intratumoral CD8 T Cell Function in Human Colorectal Cancer

2021 ◽  
Author(s):  
Marion Thibaudin ◽  
Emeric Limagne ◽  
Léa Hampe ◽  
Elise Ballot ◽  
Caroline Truntzer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rna Sequencing ◽  
Cell Function ◽  
Checkpoint Inhibitors ◽  
Ex Vivo ◽  
Immune Checkpoints ◽  
Immune Reactivity ◽  
Sequencing Data ◽  
Public Data

Abstract Microsatellite stable colorectal cancers (MSS-CRC) are resistant to anti-PD-1/PD-L1 therapy but the combination of immune checkpoints inhibitors (ICI) could be a clue to reverse resistance. Our aim was to evaluate ex vivo the capacity of the combination of atezolizumab (anti-PD-L1) and tiragolumab (anti-TIGIT) to reactivate the immune response of tumor infiltrating lymphocytes (TILs) in MSS-CRC. We analysed CRC tumor tissue and the associated blood sample in parallel. For each patient sample, extensive immunomonitoring and cytokine production were tested. We generated an ex vivo assay to study immune reactivity following immune stimulation with checkpoint inhibitors of tumor cell suspensions. Three microsatellite instable (MSI) and 13 MSS-CRC tumors were analysed. To generalize our observations, bioinformatics analyses were performed on public data of single cell RNA sequencing of CRC TILs and RNA sequencing data of TCGA. Atezolizumab alone could only reactivate T cells from MSI tumors. Atezolizumab and tiragolumab reactivated T cells in 46% of MSS-CRC samples. Reactivation by ICK was observed in patients with higher baseline frequency of Th1 and Tc1 cells, and was also associated with higher baseline T cell polyfunctionality and higher CD96 expression. CD96 expression was found in CD4 and CD8 TILs and was highly expressed in exhausted T cells. CD96 was expressed at higher levels in CMS1 and CMS4 tumors, and was related to intrinsic poor prognosis. Together these data suggest that the association of atezolizumab and tiragolumab could restore function of CD4 and CD8 TILs in MSS-CRC.

scholarly journals Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e000967 ◽  
Author(s):  
Christopher A Chuckran ◽  
Chang Liu ◽  
Tullia C Bruno ◽  
Creg J Workman ◽  
Dario AA Vignali
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Modulation ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Standard Of Care ◽  
Peripheral Tolerance ◽  
Neuropilin 1

Checkpoint blockade immunotherapy established a new paradigm in cancer treatment: for certain patients curative treatment requires immune reinvigoration. Despite this monumental advance, only 20%–30% of patients achieve an objective response to standard of care immunotherapy, necessitating the consideration of alternative targets. Optimal strategies will not only stimulate CD8+ T cells, but concomitantly modulate immunosuppressive cells in the tumor microenvironment (TME), most notably regulatory T cells (Treg cells). In this context, the immunoregulatory receptor Neuropilin-1 (NRP1) is garnering renewed attention as it reinforces intratumoral Treg cell function amidst inflammation in the TME. Loss of NRP1 on Treg cells in mouse models restores antitumor immunity without sacrificing peripheral tolerance. Enrichment of NRP1+ Treg cells is observed in patients across multiple malignancies with cancer, both intratumorally and in peripheral sites. Thus, targeting NRP1 may safely undermine intratumoral Treg cell fitness, permitting enhanced inflammatory responses with existing immunotherapies. Furthermore, NRP1 has been recently found to modulate tumor-specific CD8+ T cell responses. Emerging data suggest that NRP1 restricts CD8+ T cell reinvigoration in response to checkpoint inhibitors, and more importantly, acts as a barrier to the long-term durability of CD8+ T cell-mediated tumor immunosurveillance. These novel and distinct regulatory mechanisms present an exciting therapeutic opportunity. This review will discuss the growing literature on NRP1-mediated immune modulation which provides a strong rationale for categorizing NRP1 as both a key checkpoint in the TME as well as an immunotherapeutic target with promise either alone or in combination with current standard of care therapeutic regimens.

scholarly journals Deregulated Expression of Immune Checkpoints on Circulating CD4 T Cells May Complicate Clinical Outcome and Response to Treatment with Checkpoint Inhibitors in Multiple Myeloma Patients

2021 ◽  
Vol 22 (17) ◽  
pp. 9298
Author(s):  
Anna Kulikowska de Nałęcz ◽  
Lidia Ciszak ◽  
Lidia Usnarska-Zubkiewicz ◽  
Irena Frydecka ◽  
Edyta Pawlak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Checkpoint Inhibitors ◽  
Effector Function ◽  
Response To Treatment ◽  
Immune Checkpoints ◽  
Effective Control ◽  
Small Subset

Unlike solid-tumor patients, a disappointingly small subset of multiple myeloma (MM) patients treated with checkpoint inhibitors derive clinical benefits, suggesting differential participation of inhibitory receptors involved in the development of T-cell-mediated immunosuppression. In fact, T cells in MM patients have recently been shown to display features of immunosenescence and exhaustion involved in immune response inhibition. Therefore, we aimed to identify the dominant inhibitory pathway in MM patients to achieve its effective control by therapeutic interventions. By flow cytometry, we examined peripheral blood (PB) CD4 T cell characteristics assigned to senescence or exhaustion, considering PD-1, CTLA-4, and BTLA checkpoint expression, as well as secretory effector function, i.e., capacity for IFN-γ and IL-17 secretion. Analyses were performed in a total of 40 active myeloma patients (newly diagnosed and treated) and 20 healthy controls. At the single-cell level, we found a loss of studied checkpoints’ expression on MM CD4 T cells (both effector (Teff) and regulatory (Treg) cells) primarily at diagnosis; the checkpoint deficit in MM relapse was not significant. Nonetheless, PD-1 was the only checkpoint distributed on an increased proportion of T cells in all MM patients irrespective of disease phase, and its expression on CD4 Teff cells correlated with adverse clinical courses. Among patients, the relative defect in secretory effector function of CD4 T cells was more pronounced at myeloma relapse (as seen in declined Th1/Treg and Th17/Treg cell rates). Although the contribution of PD-1 to MM clinical outcomes is suggestive, our study clearly indicated that the inappropriate expression of immune checkpoints (associated with dysfunctionality of CD4 T cells and disease clinical phase) might be responsible for the sub-optimal clinical response to therapeutic checkpoint inhibitors in MM.

scholarly journals Elevated coinhibitory molecule TIGIT mediates T cell exhaustion in septic patients

2021 ◽  
Author(s):  
Yini Sun ◽  
Renyu Ding ◽  
Yukun Chang ◽  
Jiuming Li ◽  
Xiaochun Ma
Keyword(s):  
T Cells ◽  
T Cell ◽  
Crucial Role ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Healthy Controls ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Abstract Background: Sepsis-induced T cell exhaustion that is characterized by upregulated coinhibitory molecules and decreased cytokines release plays a crucial role in the immunosuppression during sepsis. Although PD-1 has shown a promising target to interfere with T cells dysfunction, the role of other coinhibitory receptors in sepsis remains largely elusive. Recently, it has been demonstrated that the coinhibitory molecule TIGIT more reliably identified exhausted T cells than PD-1. The aim of the study was to identify the expression of TIGIT on lymphocytes and the crucial role of TIGIT in modulating T cell function in septic patients. Methods: Twenty-five patients with sepsis and seventeen healthy controls were prospectively enrolled. Peripheral blood was obtained from septic patients within 24 hours after diagnosis of sepsis, as were healthy controls. TIGIT and other coinhibitory/costimulatory molecules expression on lymphocyte subsets was quantitated by flow cytometry. The relationship between TIGIT expression and clinical parameters was simultaneously evaluated. The function T cell from septic patients was assayed via stimulated cytokine secretion. Ex vivo functional assays were also conducted.Results: In the early stage of sepsis, patients exhibited higher levels of TIGIT on T cells relative to healthy donors, especially in the septic shock patients. Elevated frequencies of TIGIT + T cells positively correlated with the severity of organ failure and inflammatory responses in septic patients. TIGIT + T cells expressed higher levels of PD-1 and lower CD226. Further, elevated expression of TIGIT inhibited the release of cytokines including TNF, IFN-γ and IL-2 by CD4 + and CD8 + T cells. Strikingly, ex vivo blockade of TIGIT using anti-TIGIT antibody restored the frequencies of cytokine-producing T cells. Conclusions: These data illustrate TIGIT as a novel marker of exhausted T cells and suggest TIGIT may be a novel immunotherapeutic target during sepsis.

scholarly journals T-cell agonists in cancer immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e000966
Author(s):  
Yeonjoo Choi ◽  
Yaoyao Shi ◽  
Cara L Haymaker ◽  
Aung Naing ◽  
Gennaro Ciliberto ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Costimulatory Molecules ◽  
The Body

Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting cells, which ultimately leads to T-cell activation. Agonists of these costimulatory molecules have demonstrated promising results in preclinical and early-phase trials and are now being tested in ongoing clinical trials. In addition, researchers are conducting trials of combinations of such immune modulators with checkpoint blockade, radiotherapy and cytotoxic chemotherapeutic drugs in patients with advanced tumors. This review gives a comprehensive picture of the current knowledge of T-cell agonists based on their use in recent and ongoing clinical trials.

scholarly journals Breast Cancer Cells and PD-1/PD-L1 Blockade Upregulate the Expression of PD-1, CTLA-4, TIM-3 and LAG-3 Immune Checkpoints in CD4+ T Cells

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 149 ◽  
Author(s):  
Saleh ◽  
Toor ◽  
Khalaf ◽  
Elkord
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Checkpoint Inhibitors ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Immune Checkpoints ◽  
Tnbc Cell

: Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and it exhibits resistance to common breast cancer therapies. Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and its ligand, PD-L1, have been approved to treat various cancers. However, the therapeutic efficacy of targeting PD-1/PD-L1 axis in breast cancer is under clinical investigation. In addition, the mechanisms of action of drugs targeting PD-1 and PD-L1 have not been fully elucidated. In this study, we investigated the effect of human TNBC cell lines, MDA-MB-231 and MDA-MB-468, and the non-TNBC cell line, MCF-7, on the expression of immune checkpoints (ICs) on CD4+ T cell subsets, including regulatory T cells (Tregs), using a co-culture system. We also examined the effect of blocking PD-1 or PD-L1 separately and in combination on IC expression by CD4+ T cell subsets. We found that breast cancer cells upregulate the expression of ICs including PD-1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte activation gene-3 (LAG-3) in CD4+ T cell subsets. We also found that the co-blockade of PD-1 and PD-L1 further upregulates the co-expression of TIM-3 and LAG-3 on CD4+CD25+ T cells and CD4+CD25+FoxP3+Helios+ Tregs in the presence of TNBC cells, but not in non-TNBC cells. Our results indicate the emergence of compensatory inhibitory mechanisms, most likely mediated by Tregs and activated non-Tregs, which could lead to the development of TNBC resistance against PD-1/PD-L1 blockade.

scholarly journals Effect of age and sex on immune checkpoint expression and kinetics in human T cells

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Rosanne D. Reitsema ◽  
Rebeca Hid Cadena ◽  
Sander H. Nijhof ◽  
Wayel H. Abdulahad ◽  
Minke G. Huitema ◽  
...  
Keyword(s):  
Older Adults ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Ex Vivo ◽  
T Cell Subsets ◽  
Immune Checkpoints ◽  
Human T Cells ◽  
Age And Sex ◽  
Expression Kinetics

Abstract Background Immune checkpoints are crucial molecules in maintaining a proper immune balance. Even though age and sex are known to have effects on the immune system, the interplay between age, sex and immune checkpoint expression by T cells is not known. The aim of this study was to determine whether age and sex affect immune checkpoint expression by T cells and if age and sex affect the kinetics of immune checkpoint expression following ex vivo stimulation. In this study, whole blood samples of 20 healthy young adults (YA, 9 males and 11 females) and 20 healthy older adults (OA, 9 males and 11 females) were stained for lymphocyte lineage markers and immune checkpoints and frequencies of CD28+, PD-1+, VISTA+ and CD40L+ T cells were determined. Immune checkpoint expression kinetics were studied following ex vivo anti-CD3/anti-CD28 stimulation of T cells from young and older healthy adults. Results We report an age-associated increase of CD40L + CD4+ and CD40L + CD8+ T-cell frequencies, whereas CD40+ B-cell frequencies were decreased in older adults, suggesting modulation of the CD40L-CD40 interaction with age. Immune checkpoint expression kinetics revealed differences in magnitude between CD4+ and CD8+ T cells independent of age and sex. Further analysis of CD4+ T-cell subsets revealed an age-associated decrease of especially PD-1 + CD4+ memory T cells which tracked with the female sex. Conclusion Collectively, our results demonstrate that both age and sex modulate expression of immune checkpoints by human T cells. These findings may have implications for optimising vaccination and immune checkpoint immunotherapy and move the field towards precision medicine in the management of older patient groups.

scholarly journals Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months

2015 ◽  
Vol 114 (6) ◽  
pp. 891-898 ◽  
Author(s):  
Magdalena Muc ◽  
Eskil Kreiner-Møller ◽  
Jeppe M. Larsen ◽  
Sune Birch ◽  
Susanne Brix ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
T Cell ◽  
Breast Milk ◽  
Immune Responses ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Ex Vivo ◽  
Fatty Acid Desaturase ◽  
Cell Counts

AbstractBreast milk long-chain PUFA (LCPUFA) have been associated with changes in early life immune responses and may modulate T-cell function in infancy. We studied the effect of maternal fatty acid desaturase (FADS) genotype and breast milk LCPUFA levels on infants’ blood T-cell profiles and ex vivo-produced cytokines after anti-CD3/CD28 stimulation of peripheral blood mononuclear cells in 6-month-old infants from the Copenhagen Prospective Study of Asthma in Childhood birth cohort. LCPUFA concentrations of breast milk were assessed at 4 weeks of age, and FADS SNP were determined in both mothers and infants (n 109). In general, breast milk arachidonic acid (AA) levels were inversely correlated with the production of IL-10 (r −0·25; P=0·004), IL-17 (r −0·24; P=0·005), IL-5 (r −0·21; P=0·014) and IL-13 (r −0·17; P=0·047), whereas EPA was positively correlated with the counts of blood regulatory T-cells and cytotoxic T-cells and decreased T-helper cell counts. The minor FADS alleles were associated with lower breast milk AA and EPA, and infants of mothers carrying the minor allele of FADS SNP rs174556 had higher production of IL-10 (r −0·23; P=0·018), IL-17 (r −0·25; P=0·009) and IL-5 (r −0·21; P=0·038) from ex vivo-activated immune cells. We observed no association between T-cell distribution and maternal or infant FADS gene variants. We conclude that increased maternal LCPUFA synthesis and breast milk AA are associated with decreased levels of IL-5, IL-13 (type-2 related), IL-17 (type-17 related) and IL-10 (regulatory immune responses), but not with interferon-γ and TNF-α, which could be due to an effect of the maternal FADS variants on the offspring immune response transferred via breast milk LCPUFA.

IMMU-52. EFFECTS OF IMMUNE CHECKPOINT BLOCKADE ON ANTIGEN-SPECIFIC CD8+ T CELLS FOR USE IN ADOPTIVE CELLULAR THERAPY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi104-vi104
Author(s):  
Elizabeth Ogando-Rivas ◽  
Paul Castillo ◽  
Noah Jones ◽  
Vrunda Trivedi ◽  
Jeffrey Drake ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cellular Therapy ◽  
Checkpoint Inhibitors ◽  
Cell Subset ◽  
Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Effector Memory ◽  
Dependent Manner

Abstract BACKGROUND Adoptive T-cell therapies have been successfully used as treatment for patients diagnosed with advanced cancers. Unfortunately, for some refractory cancers, they have failed. To overcome this, checkpoint inhibitors have shown to rescue immune anti-tumor responses. We hypothesized that in-vitro checkpoint blockade during T-cell stimulation and expansion with RNA-pulsed dendritic cells may enhance the activity of antigen-specific T-cells and improve the efficacy of ACT platforms. METHODS Human PBMCs were isolated from CMV seropositive donors to generate DCs and pulsed them with CMVpp65-mRNA to educate T-cells in co-culture for 15-days. We targeted pp65 antigen which is ubiquitously expressed by glioblastoma cells. Three checkpoint blockade conditions were evaluated (anti-PD1, anti-Tim3 and anti-PD1+Tim3). IL2 was added every 3 days as well as the blockade antibodies. Immunephenotyping was performed on Day-0 and Day-15. Polyfunctional antigen specific responses were evaluated upon rechallenge with CMVpp65 peptides. RESULTS CMVpp65 activated CD8+ T-cells upregulate Lag3 and Tim3 (p= < 0.0001). Tim3 blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8+pp65Tetramer+ central memory, effector memory, and TEMRA T-cells. This latter T-cell subset uniquely maintain double-positive Tim3/Lag3 expression after blockade. In contrast, PD-1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN-g secretion was reduced in T-cells treated with Tim3 blockade in a dose-dependent manner (p= 0.004). CONCLUSION In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking Tim3 axis during T-cell antigen presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.

High Activity of Peripheral Blood γδ T Cells in Term and Preterm Neonates.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3897-3897
Author(s):  
Syeda F.Y. Haque ◽  
Deena L. Gibbons ◽  
Katherine Hamilton ◽  
Robert Carr ◽  
Adrian C. Hayday
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cytokine Production ◽  
Cell Function ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Preterm Neonates ◽  
Cell Compartment ◽  
Preterm Babies

Abstract The peripheral blood white cell compartment is well characterised in adults but relatively little is known in neonates. T cell function has been reported to be very different between neonates and adults. This is significant because the newborn faces the most precipitous encounter with environmental challenges. To further understand the neonatal T cell compartment, we have focussed on γδ T cells which are known to make essential contributions to the immunoprotection of very young mice. We compared γδ cells and αβ T cells from human cord and neonatal blood from term and preterm babies, and compared them with adults. We investigated T cell cultures ex vivo and derived clones. Several findings were evident. First, we confirmed that fresh neonatal αβ cells and clones are profoundly deficient in IFNγ production. Second, we showed that this is not so pronounced for γδ cells and we note that IFNγ production was higher in preterm babies than in term neonates, perhaps reflective of stress in utero. Neonatal γδ clones also made adult quantities of GM-CSF and TRAIL. We note thirdly that neonatal γδ clones make IL-4 and IL-5 (Th2 cytokines) and the immunosuppressive cytokine IL-10, which is not produced at all by adult Vγ9+ clones. Fourth, these pleiotropic activities of human neonatal γδ clones appears to be determined by the type of T cell receptor expressed. Vδ1-expressing clones have broad functional potentials whereas Vγ9-expressing clones polarise to either a Th1 or Th2 like profile. Fifth, particularly high Th1 cytokine production is observed in Vγ9-Vδ1 (DP) cells which are more common and therefore more easily cloned from neonatal versus adult blood. We conclude that the neonatal γδ cells are highly active and broader in their cytokine production than either their adult γδ cell or their neonatal αβ T cell counterparts. Thus, γδ cells should be better understood vis-à-vis perinatal vaccination regimens and the development of childhood allergies.

scholarly journals Feeding a diet devoid of choline to lactating rodents restricts growth and lymphocyte development in offspring

2016 ◽  
Vol 116 (6) ◽  
pp. 1001-1012 ◽  
Author(s):  
E. D. Lewis ◽  
S. Goruk ◽  
C. Richard ◽  
N. S. Dellschaft ◽  
J. M. Curtis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Function ◽  
Critical Period ◽  
Cell Function ◽  
Ex Vivo ◽  
Stimulation Index ◽  
Lower Proportion ◽  
Activation Markers ◽  
Immune Development

AbstractThe nutrient choline is necessary for membrane synthesis and methyl donation, with increased requirements during lactation. The majority of immune development occurs postnatally, but the importance of choline supply for immune development during this critical period is unknown. The objective of this study was to determine the importance of maternal supply of choline during suckling on immune function in their offspring among rodents. At parturition, Sprague–Dawley dams were randomised to either a choline-devoid (ChD; n 7) or choline-sufficient (ChS, 1 g/kg choline; n 10) diet with their offspring euthanised at 3 weeks of age. In a second experiment, offspring were weaned to a ChS diet until 10 weeks of age (ChD-ChS, n 5 and ChS-ChS, n 9). Splenocytes were isolated, and parameters of immune function were measured. The ChD offspring received less choline in breast milk and had lower final body and organ weight compared with ChS offspring (P<0·05), but this effect disappeared by week 10 with choline supplementation from weaning. ChD offspring had a higher proportion of T cells expressing activation markers (CD71 or CD28) and a lower proportion of total B cells (CD45RA+) and responded less to T cell stimulation (lower stimulation index and less IFN-γ production) ex vivo (P<0·05). ChD-ChS offspring had a lower proportion of total and activated CD4+ T cells, and produced less IL-6 after mitogen stimulation compared with cells from ChS-ChS (P<0·05). Our study suggests that choline is required in the suckling diet to facilitate immune development, and choline deprivation during this critical period has lasting effects on T cell function later in life.

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