Successful treatment of posttransplantation lymphoproliferative disorder (PTLD) following renal allografting is associated with sustained CD8+ T-cell restoration

Posttransplantation lymphoproliferative disorder (PTLD) is a life-threatening Epstein-Barr virus (EBV)–associated B-cell malignancy occurring in 1% to 2% of renal transplantation patients. Host- and PTLD-related factors determining the likelihood of tumor response following reduction of immune suppression (IS) and antiviral therapy remain largely unknown. Standard therapy for PTLD is not well established. Eleven consecutive renal transplantation patients who developed EBV-positive PTLD 8 to 94 months after allografting were uniformly treated with acyclovir and IS reduction. All PTLDs were EBV-positive diffuse large B-cell lymphomas. Ten patients (91%) obtained a durable complete response (CR), and 9 (82%) have remained in continuous CR with a median follow-up of 29 months. Five patients (45%) lost their allograft. Of these, 4 patients had PTLD affecting the transplanted kidney. Peripheral blood CD8+ T cells increased significantly (P = .0078) from baseline in 8 responders available for analysis. One of 2 patients whose absolute CD8+ T-cell count subsequently dropped to baseline after IS reduction relapsed. The expanded CD8+ T cells from 2 responders specifically recognized an immunodominant peptide from the EBV lytic gene BZLF-1. Another lytic EBV gene, thymidine kinase, was expressed in all 8 PTLDs tested. IS reduction and antiviral therapy for PTLD after renal transplantation is a highly successful therapeutic combination, but the risk of graft rejection is significant, particularly in patients with PTLD involving the renal allograft. A sustained expansion of CD8+ T cells and a cellular immune response to EBV lytic antigens may be important for PTLD clearance in renal transplantation patients.

Download Full-text

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

10.1101/2021.07.14.452381 ◽

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.

Download Full-text

Obligatory Requirement for Antibody in Recovery from a Primary Poxvirus Infection

Journal of Virology ◽

10.1128/jvi.00116-06 ◽

2006 ◽

Vol 80 (13) ◽

pp. 6339-6344 ◽

Cited By ~ 73

Author(s):

Geeta Chaudhri ◽

Vijay Panchanathan ◽

Horst Bluethmann ◽

Gunasegaran Karupiah

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cd8 T Cells ◽

Cell Function ◽

Cd8 T Cell ◽

T Cell Response ◽

Ectromelia Virus ◽

B Cell Function

ABSTRACT To understand the correlates of protective immunity against primary variola virus infection in humans, we have used the well-characterized mousepox model. This is an excellent surrogate small-animal model for smallpox in which the disease is caused by infection with the closely related orthopoxvirus, ectromelia virus. Similarities between the two infections include virus replication and transmission, aspects of pathology, and development of pock lesions. Previous studies using ectromelia virus have established critical roles for cytokines and effector functions of CD8 T cells in the control of acute stages of poxvirus infection. Here, we have used mice deficient in B cells to demonstrate that B-cell function is also obligatory for complete virus clearance and recovery of the host. In the absence of B cells, virus persists and the host succumbs to infection, despite the generation of CD8 T-cell responses. Intriguingly, transfer of naive B cells or ectromelia virus-immune serum to B-cell-deficient mice with established infection allowed these animals to clear virus and fully recover. In contrast, transfer of ectromelia virus-immune CD8 T cells was ineffective. Our data show that mice deficient in CD8 T-cell function die early in infection, whereas those deficient in B cells or antibody production die much later, indicating that B-cell function becomes critical after the effector phase of the CD8 T-cell response to infection subsides. Strikingly, our results show that antibody prevents virus from seeding the skin and forming pock lesions, which are important for virus transmission between hosts.

Download Full-text

Functional Signatures Revealed By Deep Phenotyping of CMV-Specific CD8+ T Cells Predict Risk of Early CMV Reactivation after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v130.suppl_1.746.746 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 746-746

Author(s):

Jose F Camargo ◽

Eric Wieder ◽

Erik Kimble ◽

Cara Benjamin ◽

Despina Kolonias ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antiviral Therapy ◽

Cd8 T Cells ◽

Predictive Value ◽

Cd8 T Cell ◽

Low Grade ◽

Need For Treatment ◽

Predicted Risk ◽

Cmv Reactivation

Abstract CMV is the most clinically significant viral infection in HCT recipients. Control CMV reactivation after HCT is highly dependent on CMV-specific T cells. Despite dramatic technical advances, the clinical utility of functional assays of virus-specific T cells to predict CMV reactivation following HCT remains to be established. Using 13-color flow cytometry, we studied CD8+T cell responses to pp65 and IE-1 CMV peptide stimulation in cryopreserved PBMC from three clinically distinct subgroups (n=10 each) of HCT patients: 1) Elite Controllers (EC) : CMV seropositive (R+) recipients who never reactivated CMV based on weekly surveillance testing; 2) Spontaneous Controllers (SC): CMV R+ recipients who spontaneously resolved low-grade viremia (<200 IU/mL) without antiviral therapy; and 3) Non-controllers (NC): CMV R+ recipients who experienced high-grade CMV viremia (>1,000 IU/mL) requiring antiviral therapy. NC had lower numbers of CD8+ T cells that simultaneously produced 3-4 cytokines in response to CMV peptides compared to EC and SC (18, 26 and 34%, respectively) suggesting that progressive CMV viremia is associated with loss of CD8+ T cell polyfunctionality. Among 15 possible cytokine signatures, we identified two CMV-specific CD8+ T cell cytokine signatures, measured at day +30, that were strongly associated with the risk of CMV reactivation (Fig. 1): i) the non-protective signature (NPS) consisting of IL-2negIFNγposTNFαnegMIP-1βpos CD8+ T cells was positively associated with CMV reactivation (4.9% of CMV-specific CD8+ T cells vs. 19.4 P=0.002 for EC vs. SC/NC; 4.9 vs. 10.8 P=0.02 for EC vs. SC; 4.9 vs. 22.8 P=0.005 for EC vs. NC for pp65 stimulated cells; similar trends were observed in IE-1 stimulated cells); ii) the protective signature (PS) consisted of quadruple producers (IL-2posIFNγposTNFαposMIP-1βpos), and was significantly reduced among NC vs. SC following pp65 and IE-1 stimulation (0.05% of CMV-specific CD8+ T cells vs. 2.85 for pp65, P= 0.02; 0 vs. 1.25 for IE-1, P= 0.02); this association was also found in superantigen-stimulated cells. Production of IFNγ alone or in combination did not predict reactivation (P=0.49). Since NC trended toward more frequent recurrence of CMV viremia compared to SC (60 vs. 10%, respectively; P=0.06), we explored the association between PS and NPS and number of episodes of CMV reactivation (Fig. 1). We observed a significant stepwise increase in the levels of the NPS in pp65-stimulated cells in patients who experienced 0 vs. 1 and ≥2 episodes of CMV reactivation (4.9, 18.3 P=0.002, and 22.4 P=0.06). In addition, patients with ≥2 episodes of CMV had the lowest levels of the PS across groups (0 vs. 2.2% for ≥2 vs. 1 episode P=0.02). Similar trends were observed in IE-1 stimulated cells. Whereas T-cell depletion, aGVHD, lymphoid malignancy and CMV donor serostatus were not associated with risk of CMV in this small cohort, a NPS >10% was associated with increased risk of CMV reactivation (OR: 21, CI95 2-215; P=0.01) and need for treatment (OR: 14, CI95 1.5-137; P=0.02); and a PS >2% was associated with trend toward reduced risk of need for treatment (OR: 0.1, CI95 0.01-1.05; P=0.06). Multivariable modeling was not performed due to sample size. Time to event curves showed that high levels of NPS (>10%) predicted risk of CMV reactivation (log-rank P=0.0002). This remained true in analyses restricted to patients with CMV reactivation after day 30 (log-rank P=0.01). High levels of NPS or low levels of PS (<2%) predicted risk of need for treatment (log-rank P=0.003 and P=0.04, respectively). Combination of the PSlow/NPShigh had the highest predictive value for risk of need for treatment (log-rank P <0.0001; fig. 2). 18 graft products were available. As expected CMV-specific responses were not detected in grafts from CMV seronegative donors. Among the 9 CMV seropositive grafts, NPS expression was null across groups suggesting that the NPS is an immune phenotype that is absent in healthy donors; there was a stepwise decrease in the number of quadruple producer CD8+ T cells in CMV seropositive grafts for EC, SC and NC: 3.4 (n=3), 2 (n=4) and 0 (n=2), respectively, suggesting that donor PS might influence recipient reactivation. In conclusion, we have identified two novel CMV-specific CD8+ T cell cytokine signatures with robust predictive value for risk of CMV reactivation and need for treatment. These biomarkers might be useful in guiding clinical decision making in HCT recipients. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Lack of B Lymphocytes Enhances CD8 T Cell-Mediated Resistance against Respiratory Viral Infection but Compromises Memory Cell Formation

Journal of Virology ◽

10.1128/jvi.01877-19 ◽

2019 ◽

Vol 94 (3) ◽

Author(s):

Pritesh Desai ◽

Jessica Stanfield ◽

Vikas Tahiliani ◽

Georges Abboud ◽

Shahram Salek-Ardakani

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Viral Infection ◽

B Cell ◽

Cd8 T Cells ◽

Host Resistance ◽

Memory Cell ◽

Cd8 T Cell ◽

Respiratory Viral Infection

ABSTRACT Following a respiratory virus infection, CXCR3hi CX3CR1lo and CXCR3lo CX3CR1hi CD8 T cells localize to different compartments within the lung and play an important role in host resistance, but mechanisms governing their optimal generation are poorly defined. We serendipitously found that B cell-deficient (μMT−/−) mice were highly resistant to lethal infection with a virulent poxvirus strain and that depletion of CD8 T cells rendered these mice susceptible to infection. B cells were not required for the expansion of virus-specific CD8 T cells, but a greater proportion of activated CD8 T cells acquired an effector-like CXCR3lo CX3CR1hi phenotype in the absence of B cells. After recovery from infection, CD8 T cells in μMT−/− mice contracted normally but failed to survive and seed the memory cell pool in both the lungs and spleen. These findings reveal a previously unappreciated role for B cells in regulating the balance between CD8 T cell-mediated resistance against respiratory viral infection and memory cell development. IMPORTANCE B cells play critical role in host resistance against many respiratory viral infections. However, the role of B cells beyond antibody-producing cells is less well defined. In this study, we made a surprising observation that mice lacking B cells were more resistant to respiratory infection with vaccinia virus than wild-type mice. This enhanced resistance was mediated by CD8 T cells because when we depleted CD8 T cells in B cell-deficient mice, these mice were unable to survive the infection. Interestingly, CD8 T cells in B cell-deficient mice were skewed more toward effector phenotype and less toward memory phenotype, which resulted in severely compromised memory CD8 T cell development. Thus, our study shows a novel role of B cells as regulators of CD8 T cell-mediated host resistance and memory CD8 T cell formation during respiratory viral infection.

Download Full-text

The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

Frontiers in Immunology ◽

10.3389/fimmu.2021.665718 ◽

2021 ◽

Vol 12 ◽

Author(s):

Caterina Veroni ◽

Francesca Aloisi

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cd8 T Cells ◽

Epstein Barr Virus ◽

Cd8 T Cell ◽

Barr Virus ◽

Epstein Barr

The cause and the pathogenic mechanisms leading to multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), are still under scrutiny. During the last decade, awareness has increased that multiple genetic and environmental factors act in concert to modulate MS risk. Likewise, the landscape of cells of the adaptive immune system that are believed to play a role in MS immunopathogenesis has expanded by including not only CD4 T helper cells but also cytotoxic CD8 T cells and B cells. Once the key cellular players are identified, the main challenge is to define precisely how they act and interact to induce neuroinflammation and the neurodegenerative cascade in MS. CD8 T cells have been implicated in MS pathogenesis since the 80’s when it was shown that CD8 T cells predominate in MS brain lesions. Interest in the role of CD8 T cells in MS was revived in 2000 and the years thereafter by studies showing that CNS-recruited CD8 T cells are clonally expanded and have a memory effector phenotype indicating in situ antigen-driven reactivation. The association of certain MHC class I alleles with MS genetic risk implicates CD8 T cells in disease pathogenesis. Moreover, experimental studies have highlighted the detrimental effects of CD8 T cell activation on neural cells. While the antigens responsible for T cell recruitment and activation in the CNS remain elusive, the high efficacy of B-cell depleting drugs in MS and a growing number of studies implicate B cells and Epstein-Barr virus (EBV), a B-lymphotropic herpesvirus that is strongly associated with MS, in the activation of pathogenic T cells. This article reviews the results of human studies that have contributed to elucidate the role of CD8 T cells in MS immunopathogenesis, and discusses them in light of current understanding of autoreactivity, B-cell and EBV involvement in MS, and mechanism of action of different MS treatments. Based on the available evidences, an immunopathological model of MS is proposed that entails a persistent EBV infection of CNS-infiltrating B cells as the target of a dysregulated cytotoxic CD8 T cell response causing CNS tissue damage.

Download Full-text

CD8+ /ICOS+ /CXCR5+ Tumor Infiltrating T-CELLS (CD8fc) Sharing Functional Similarities With TFH CELLS ARE Present In Classical Hodgkin’S Lymphoma Tissues Displaying A Specific “MIXED NODULARITY” Pattern

Blood ◽

10.1182/blood.v122.21.4233.4233 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4233-4233 ◽

Cited By ~ 1

Author(s):

Suong Le Thi ◽

Florence Broussais ◽

Reda Bouabdallah ◽

Françoise gondois-Rey ◽

Luc Xerri ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cd8 T Cells ◽

Cell Lymphoma ◽

Cell Subset ◽

B Cell Lymphoma ◽

Cd8 T Cell ◽

Tissue Samples ◽

Tfh Cells

Abstract We have previously reported that some classical Hodgkin’s Lymphoma (cHL) tissues display a gene signature evocative of a Th1 immune reaction. In order to better characterize this process, immune cell subsets were isolated from cHL tissue samples (n=21) using a powerful multicolor flow cytometry method, in parallel with cell sorting. Fresh tissue samples from follicular B cell lymphoma (FL, n=8), diffuse large cell B cell lymphoma (n=8) and reactive lymphadenitis (n= 5) were used as controls. In 4 cLH cases, we observed a significant proportion of activated CD8+ T-cells expressing ICOS and CXCR5 at high levels. The presence of either CD8+/ICOS+/CXCR5- T cells or CD8+/ICOS +/ CXCR5+ T-cells was a specific feature of HL tissues since it was absent from B-cell lymphomas, T-cell lymphomas and reactive tissues. In contrast, CD8+/CXCR5+ T-cells were found not only in cHL, but also in most other samples analyzed. Further phenotypic characterization showed that the CD8+/ICOS +/ CXCR5+ T cells expressed markers associated with CD4 TFH cells, like PD1, BTLA, bcl-6 and IL-21. Under stimulation, they expressed only low levels of IFNG, granzyme B and perforin, and thus do not fulfill the criteria of activated cytotoxic effectors. Co-culture experiments showed a dramatic enhancement of CD86 expression on stimulated B-cells in contact with CD8+/ICOS +/ CXCR5+ T cells. This effect was similarly observed after co-culture with CD4+TFH cells. The 4 cHL cases associated with CD8+/ICOS +/ CXCR5+ T-cells contained CD30+ CD15+ EBV+ Reed Sternberg cells (RSC). They were characterized a nodular non-sclerotic pattern reminiscent of the nodular lymphocyte-rich classical HL (NLRCHL) subtype, but also displayed a specific “mixed nodularity” feature. Various nodules were indeed observed, including reactive germinal centers (GC) partly colonized by RSC co-localizing with CD8+/ICOS+ T-cells, suggesting an early GC invasion triggering an intra-follicular CD8 T-cell reaction. Other nodules were composed of a high number of RS cells admixed with numerous CD8+/ICOS+ T-cells. This “mixed nodularity” pattern was absent in the other HL cases. Altogether, our results point out a previously unrecognized intra- follicular CD8 T-cell subset sharing phenotypic and functional features with CD4 TFH, that we have thus considered as putative “follicular cytotoxic” CD8 T-cells (TFC). This cell subset appears to be specifically associated with EBV+ cHL tissues with unusual histo-phenotypic features, which may probably reflect a strong CD8 activation process. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

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

Journal of Virology ◽

10.1128/jvi.78.13.6827-6835.2004 ◽

2004 ◽

Vol 78 (13) ◽

pp. 6827-6835 ◽

Cited By ~ 42

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.

Download Full-text

Biomarker Analysis of a Phase Ia/Ib Open-Label, Multicentre Study of Tiragolumab or Tiragolumab + Rituximab in Patients with Relapsed or Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL)

Blood ◽

10.1182/blood-2021-147773 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1337-1337

Author(s):

Shannon Ruppert ◽

Vaikunth Cuchelkar ◽

Raymond Meng ◽

Eunpi Cho ◽

Sean Lear ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cd8 T Cells ◽

Cell Activation ◽

Nk Cell ◽

Single Agent ◽

Cd8 T Cell ◽

Cd25 Expression ◽

Cd69 Expression

Abstract Background: NHL is the most common hematologic malignancy in adults, with follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) being the most common subtypes. Despite therapeutic advances, most patients will experience relapse. New treatments are therefore needed to improve the outcome of patients with R/R NHL. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a well-known immune inhibitory receptor expressed on the surface of activated T cell and natural killer (NK)-cell subsets. TIGIT is expressed at higher levels than other checkpoints in intratumoral T cells in NHL and is highly correlated with PD-1 expression and T cell infiltration. This phase Ia/Ib trial (NCT04045028) evaluated the safety and pharmacokinetics of the anti-TIGIT agent, tiragolumab, alone or in combination with rituximab. Methods: Patients were recruited with histologically confirmed B-cell NHL whose disease has relapsed or failed to respond to ≥2 prior systemic treatment regimens, had ECOG PS 0-1, adequate hematologic and end organ function, and no history of CNS lymphoma. Patients received tiragolumab 600 mg IV Q3W with or without rituximab 375 mg/m 2 IV for the initial dose and 1400 mg SC rituximab/23400 U rHuPH20 QW for 8 doses. Here, we evaluate biomarker data collected from patients with R/R NHL dosed with tiragolumab as a single agent or in combination with rituximab via flow cytometry and IHC. Results: At data cut-off (July 2021), biomarker data had been collected from 14 patients with NHL. Baseline CD8 T cell density within the tumor region evaluated via IHC for these patients was between 500-6000 per mmA 2. In the peripheral blood of the 7 patients dosed with the combination of tiragolumab and rituximab, CD8 T cell expansion observed via absolute counts by flow cytometry was seen in 2 patients. Among the 7 patients, NK/NKT CD25 expression remained unchanged and a modest increase in NK CD69 expression was sustained above baseline in 1 patient. Overall, transient NK cell activation via increased CD69 expression was observed in 2 patients, which would be expected from the addition of rituximab. Increased PD-L1 expression was observed on multiple lymphocyte subsets in 4 of 7 patients in this cohort. Of the 7 patients who received single agent tiragolumab, trends in increased CD69 expression on NKs were observed in 4 patients and NK/NKT CD25 expression in 3 patients. A modest CD8 T cell activation, via increased CD69 expression, was observed in 2 patients, though T cell counts remained unchanged. At baseline, TIGIT was abundantly expressed on peripheral blood CD8 T cells, while co-expression of exhaustion markers on CD8 T cells was less widely observed. Although one patient experienced a sustained response, no other patients achieved clinical benefit. This heavily pretreated 65-year-old female patient with FL had an objective partial response (best overall response), determined via Lugano criteria, with a response duration on single agent tiragolumab for 11 months. The patient had a two-fold upregulated CD69 expression on NKs and sixty-three-fold CD25 upregulated expression on NK/NKTs, as well as increased frequencies of PD-L1+ on immune cells over course of treatment. In this patient, relatively higher TIGIT and lower expression of exhaustion markers on CD8 T cells were observed at baseline and over treatment compared to other patients analyzed. Conclusions: In this study, tiragolumab as a single agent and in combination with rituximab was seen to result in increased PD-L1 expression on multiple lymphocyte subsets (including B cells, CD4/CD8 T cells, and NKs), which support the combination of tiragolumab with PD-L1/PD-1 inhibitors. Increases in NK/NKT CD25 expression could suggest a tiragolumab-mediated increase in proliferative potential but further investigations are needed to confirm. A patient with R/R FL in this study was observed to have the first documented objective response to single agent tiragolumab in this disease indication, suggesting biomarker-driven combination strategies may be important in this population. Disclosures Ruppert: Genentech, Inc.: Current Employment. Cuchelkar: Genentech, Inc.: Current Employment. Meng: Genentech, Inc.: Current Employment. Cho: Genentech, Inc.: Current Employment; F. Hoffmann La Roche, Ltd: Current holder of individual stocks in a privately-held company. Lear: Genentech, Inc.: Current Employment. Wong: Genentech, Inc.: Current Employment. Raval: Genentech, Inc.: Ended employment in the past 24 months; Arcus Bioscience: Current Employment, Current holder of individual stocks in a privately-held company. Nouet: F. Hoffmann La Roche, Ltd: Current Employment.

Download Full-text

IMMU-36. B CELL-VACCINE ELICITS LONG TERM IMMUNITY AGAINST GLIOBLASTOMA VIA ACTIVATION AND DIFFERENTIATION OF TUMOR-SPECIFIC CD8+ MEMORY T CELLS

Neuro-Oncology ◽

10.1093/neuonc/noab196.395 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi100-vi100

Author(s):

David Hou ◽

Brandyn Castro ◽

Mark Dapash ◽

Aida Rashidi ◽

Peng Zhang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Tumor Bearing

Abstract While immunotherapy is used clinically to treat many cancers, its translation into brain tumors remains elusive. The importance of B cells in cancer immunity has become increasingly clear, and we previously developed a B cell-based cellular vaccine (BVax) against glioblastoma (GBM) by further activating 4-1BBL+ B cells with CD40 agonism and IFNγ. BVax were characterized as professional antigen-presenting cells (APCs) that promote CD8+ T cell migration and persistence in murine tumor-bearing brains. This study seeks to understand the mechanisms underlying BVax-induced CD8+ T cell fitness in the tumor microenvironment. Initial transcriptomic analysis highlighted that Bvax express high levels of IL15Rα, indicating their potential ability to trans-present IL15. Considering IL15 trans-presentation is fundamental in T-cell memory differentiation, we used BVax to induce T cell activation in the presence of exogenous IL15. BVax were better capable of activating antigen-specific CD8+ T cells and promoting a memory phenotype when compared to other professional APCs such as dendritic cells (DCs). T cell receptor (TCR) CDR3β sequencing showed that BVax expanded a number of TCR clones in-vitro that were found in brains of CT2A tumor-bearing mice in-vivo. These BVax-activated CD8+ T cells displayed a stronger antigen recall response and unique metabolic profile compared to DC-activated CD8+ T cells as shown by metabolomic analysis of tumor-infiltrating CD8+ T cells. When comparing the anti-tumor effects of CD8+ T cells activated by various APCs, BVax with exogenous IL15 promoted CD8+ T cells that displayed the most potent cytotoxicity against GBM cells in-vitro. Collectively, this study suggests that the IL15/IL15Rα axis and interactions with CD8+ T cell are key factors of BVax therapy in promoting a robust survival benefit and long-term immunologic memory against GBM in preclinical models. Additionally, the development of T cell therapies based on B cell licensing can be a promising future approach for glioblastoma therapy.

Download Full-text

Pathogenic CD8 T cells defined by longitudinal liver sampling in chronic hepatitis B patients starting antiviral therapy

10.1101/2021.12.16.21267870 ◽

2021 ◽

Author(s):

Shirin Nkongolo ◽

Deeqa Mahamed ◽

Adrian Kuipery ◽

Juan D. Sanchez Vasquez ◽

Samuel C. Kim ◽

...

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

T Cell ◽

Hepatitis B ◽

Antiviral Therapy ◽

Chronic Hepatitis B ◽

Liver Damage ◽

Cd8 T Cells ◽

Human Liver ◽

Cd8 T Cell

Accumulation of activated immune cells results in non-specific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. We enrolled 15 CHB patients with active liver damage to receive antiviral therapy, and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8 T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8 T cells, resulting in non-specific Fas ligand-mediated killing of target cells. These results define a CD8 T cell population in the human liver that can drive pathogenesis, and a key pathway involved in their function in CHB patients.

Download Full-text