scholarly journals 510 SO-C101, a high-affinity IL-15Rbg agonist, induces safe and potent anti-tumor immune activities in patients with solid tumors and supports further clinical investigations

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A541-A541
Author(s):  
Lenka Palová
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Immune Cells ◽  
Immune Cell ◽  
Clear Correlation ◽  
High Affinity ◽  
Link Type ◽  
Clinical Investigations ◽  
Dose Dependent

BackgroundSO-C101 is a high affinity superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi<+/sup> domain, representing a promising clinical candidate for the treatment of cancer. SO-C101 specifically stimulates natural killer (NK) cells and memory CD8<+/sup> T cells with no significant expansion and activation of regulatory T cell compartment.MethodsBlood and tumor samples from patients with advanced/metastatic solid tumors included in Phase clinical I study (NCT04234113) were analysed by flow cytometry, immunohistochemistry and NanoString analyses for the activation of immune cells induced by SO-C101 monotherapy or in combination with pembrolizumab.ResultsSO-C101 showed a dose-dependent activity in blood of all patients with no clear correlation between the increase of immune cell proliferation and counts in blood and recruitment of immune cells into the tumor tissue. SO-C101 (RLI-15) as a monotherapy or in combination with pembrolizumab increases immune cell infiltration in tumors in clinically responsive patients in Phase clinical I study (NCT04234113) which is accompanied by NK and CD8<+/sup> T cell activation and cytotoxicity, increased proinflammatory chemokines and IFN-gamma signaling genes signatures.ConclusionsAll patients showed dose-dependent pharmacodynamic responses in blood, however SO-C101 activity in the tumor microenvironment might be pivotal for the therapeutic success. Favorable safety profile and potent anti-tumor immune activities in patients with solid tumors support further clinical investigations.Trial RegistrationNCT04234113Ethics ApprovalThis study was approved by the FDA (IND 140011) and by the Ethics Boards of participating institutions. The participants provided written informed consent.

scholarly journals 368 Consistent pattern of immune activation induced by oncolytic adenovirus ONCOS-102 across diverse types of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A396-A396
Author(s):  
Lukasz Kuryk ◽  
Anne-Sophie Moller ◽  
Sandeep Kumar ◽  
Alexander Shoushtari ◽  
Luis Paz Ares ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Clinical Importance ◽  
Oncolytic Adenovirus ◽  
Link Type ◽  
Tumor Types

BackgroundSolid tumors exhibit highly variable compositions of immune infiltrates. Therapeutic compounds driving uniform remodeling of tumor microenvironment (TME) across tumor types may improve the efficacy of cancer immunotherapy. ONCOS-102, a granulocyte-macrophage colony stimulating factor (GM-CSF)-expressing oncolytic adenovirus (Ad5/3-D24-GMCSF), was tested for its safety, therapeutic efficacy and capacity to remodel TME in recently completed phase I/II clinical studies in anti-PD-1 refractory melanoma (NCT03003676) and malignant pleural mesothelioma (MPM) (NCT02879669).MethodsBiopsies were obtained from tumor lesions of patients treated with intra-tumoral injections of ONCOS-102 in combination with chemotherapy or pembrolizumab for MPM and melanoma, respectively. Tumor immune infiltrates were analyzed by immunohistology using several antibody panels. On-treatment biopsies were compared to paired baseline samples as wells as to samples from control patients treated with chemotherapy alone in the case of MPM. Gene expression data obtained by next generation RNA sequencing were used to complement the immunohistology analysis and all results were correlated to clinical outcomes.ResultsComparative TME analysis of anti-PD-1 refractory melanoma and MPM tumors revealed noticeably lower baseline T-cell infiltration in mesothelioma. Thus, fractions of CD8+ T-cells were significantly below 10% in 80% of MPM biopsies while approaching or exceeding this level in 60% of melanoma baseline samples. Comparison of tumor biopsies obtained at baseline or on-treatment, demonstrated increased infiltration by both CD4+ and CD8+ T-cells in large proportions of melanoma (CD4+: 13/20 (65%); CD8+: 16/19 (84%) and MPM (CD4+: 10/15 (67%); CD8+: 9/15 (60%) tumor lesions in response to ONCOS-102. Frequencies of cytotoxic T-cells with high granzyme-B expression also increased in response to the treatment in both tumor types, in particular when assessed as percentage of total CD8+ T-cells. Other observed changes induced by ONCOS-102 in samples taken from CR, PR and SD patients with MPM or melanoma included increased CD8/Treg ratio and modulation of PD-L1 expression. Biological and clinical importance of these findings was further supported by correlation between modulation of several subsets of genes related to the process of T-cell activation, such as cytotoxic granule components and co-stimulatory molecules, and clinical response to ONCOS-102 in melanoma and both tumor response and overall survival in MPM patients.ConclusionsONCOS-102 drives pro-inflammatory modulation of immune TME across tumor types of different origins, anatomical locations and immunological baseline characteristics. Our data support potential of ONCOS-102 to serve as a potent immune sensitizing agent in combination therapies with various classes of immunomodulatory compounds and chemotherapy.

scholarly journals GABAA receptor α4-subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model

2017 ◽  
Vol 313 (2) ◽  
pp. L406-L415 ◽  
Author(s):  
Gene T. Yocum ◽  
Damian L. Turner ◽  
Jennifer Danielsson ◽  
Matthew B. Barajas ◽  
Yi Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Asthma Model

Emerging evidence indicates that hypnotic anesthetics affect immune function. Many anesthetics potentiate γ-aminobutyric acid A receptor (GABAAR) activation, and these receptors are expressed on multiple subtypes of immune cells, providing a potential mechanistic link. Like immune cells, airway smooth muscle (ASM) cells also express GABAARs, particularly isoforms containing α4-subunits, and activation of these receptors leads to ASM relaxation. We sought to determine if GABAAR signaling modulates the ASM contractile and inflammatory phenotype of a murine allergic asthma model utilizing GABAAR α4-subunit global knockout (KO; Gabra40/0) mice. Wild-type (WT) and Gabra4 KO mice were sensitized with house dust mite (HDM) antigen or exposed to PBS intranasally 5 days/wk for 3 wk. Ex vivo tracheal rings from HDM-sensitized WT and Gabra4 KO mice exhibited similar magnitudes of acetylcholine-induced contractile force and isoproterenol-induced relaxation ( P = not significant; n = 4). In contrast, in vivo airway resistance (flexiVent) was significantly increased in Gabra4 KO mice ( P < 0.05, n = 8). Moreover, the Gabra4 KO mice demonstrated increased eosinophilic lung infiltration ( P < 0.05; n = 4) and increased markers of lung T-cell activation/memory (CD62L low, CD44 high; P < 0.01, n = 4). In vitro, Gabra4 KO CD4+ cells produced increased cytokines and exhibited increased proliferation after stimulation of the T-cell receptor as compared with WT CD4+ cells. These data suggest that the GABAAR α4-subunit plays a role in immune cell function during allergic lung sensitization. Thus GABAAR α4-subunit-specific agonists have the therapeutic potential to treat asthma via two mechanisms: direct ASM relaxation and inhibition of airway inflammation.

316 EVICTION Study: Preliminary results in solid tumor patients with ICT01, a first-in-class, gamma9 delta2 T cell activating antibody targeting butyrophilin-3A

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A342-A342
Author(s):  
Aurelien Marabelle ◽  
Christiane Jungels ◽  
Johann De Bono ◽  
Norbert Vey ◽  
Martin Wermke ◽  
...  
Keyword(s):  
T Cells ◽  
Informed Consent ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activity ◽  
Ethics Committee ◽  
Preliminary Results ◽  
Link Type ◽  
Tumor Biopsies

BackgroundGamma9 Delta2 (γ9δ2) T cells are an important component of the innate anti-tumor immune response whose infiltration into solid tumors has been associated with a positive prognosis, making γ9δ2 T cells an attractive target for the next generation of cancer immunotherapy. Butyrophilins (BTNs) are a family of immune checkpoint molecules that regulate γ9δ2 T cell activity, including BTN3A that is a potent endogenous activator of γ9δ2 T cells following phosphoantigen (pAg) binding to the intracellular domain of BTN3A1. This observation led to the design and development of ICT01, a humanized, monoclonal antibody that binds all 3 isoforms of BTN3A1/A2/A3 and induces pAg-independent γ9δ2 T cell activation, for the treatment of patients with solid or hematologic tumors.MethodsEVICTION (www. clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31) is a first-in-human, two-part, open-label, clinical study to assess the safety, tolerability and activity of intravenous doses of ICT01 as monotherapy and in combination with pembrolizumab, in patients with advanced-stage, relapsed/refractory cancer. Following Competent Authority and Ethics Committee approvals, the study is being conducted at cancer centers in France, Belgium, Spain, Germany, and the UK. Patients provide signed informed consent prior to screening. Eligible patients receive ICT01 (Range: 20 µg to 200 mg) every 3 weeks with blood samples collected at multiple timepoints for immunophenotyping and cytokine analysis (IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-13, TNFα). Tumor biopsies are collected at baseline and Day 28 and stained by immunohistochemistry for BTN3A, γ9δ2 T cells and other markers of anti-tumor immunity.ResultsCohort 1 comprising 6 patients with solid tumors (3 Colorectal, 1 Pancreatic, 1 Ovarian, 1 Melanoma) has been enrolled and treated with ICT01 doses ranging from 20 to 700 µg. No dose-limiting toxicities or related SAEs have been reported. Target occupancy on T cells at 4 hours post first dose was 10% at 70 µg (n=1), 31% at 200 µg (n=2) and 34% at 700 µg (n=2), which was reflected at 24 hours post dose by a 73%, 91% and 97% decrease from baseline in the number of circulating γ9δ2 T cells, respectively. On Day 7, γ9δ2 T cells remained decreased by 37%, 75% and 76%, respectively. There were no effects on CD4 or CD8 T cells, NK cells, or B cells. Transient increases in IFNγ, secreted by activated γ9δ2 T cells, were observed in 4/6 patients. No cytokine release syndrome was observed. Data from the paired tumor biopsies are still being generated and will be presented.ConclusionsThe preliminary results demonstrate that ICT01 has the potential to safely activate the innate anti-tumor potential of γ9δ2 T cells through BTN3A.Acknowledgements.Trial Registrationwww.clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31Ethics ApprovalThis study was approved by the following Ethics Committees: COMITE DE PROTECTION DES PERSONNES, Sud-Méditerranée V (Gustave Roussy, IPC), Comité d’Ethique Institut Jules Bordet, COMITÉ DE ÉTICA DE INVESTIGACIÓN CLÍNICA CON MEDICAMENTOS del Hospital Universitari Vall d’Hebron, Ethikkommission an der TU Dresden, HRA London-Surrey Borders Research Ethics Committee.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

398 AGEN1181, an Fc engineered anti-CTLA-4 antibody, demonstrates clinical activity, alone or in combination with balstilimab (anti-PD-1), and broadens the therapeutic potential of CTLA-4 therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A423-A423
Author(s):  
Steven O’Day ◽  
Anthony El khoueiry ◽  
Chethan Ramamurthy ◽  
Andrea Bullock ◽  
Irina Shapiro ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Models ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Control ◽  
Clinical Activity ◽  
Small Subset ◽  
Tumor Bearing Mouse ◽  
High Affinity ◽  
Tumor Bearing

BackgroundImmune checkpoint therapies targeting CTLA-4, alone, or in combination with anti-PD-1 have shown durable responses in cancer patients. However, responses are limited to a small subset of patients in the most common immunogenic cancers. Here we describe, a novel anti-CTLA-4 antibody, AGEN1181, with enhanced FcyR-dependent functionality that harnesses a novel mechanism of action to promote superior T cell activation and anti-cancer immunity. Concordant with preclinical findings, we report preliminary safety, pharmacodynamic and efficacy data from a phase 1 study of AGEN1181 (NCT03860272), alone or in combination with balstilimab (anti-PD-1 antibody) in a range of immunogenic and non-immunogenic tumors.MethodsThe functional activity of AGEN1181 or AGEN1181-like mouse surrogate were assessed in primary cell-based assays or in PD-1 refractory syngeneic tumor-bearing mouse models (B16F10 or KPC pancreatic tumor). Efficacy was evaluated as monotherapy, or in combination with anti-PD-1, focal radiation or chemotherapy. In an ongoing phase I study, AGEN1181 is administered intravenously once every 3- or 6-weeks as monotherapy (0.1–4 mg/kg), or every 6-weeks (1–4 mg/kg) in combination with balstilimab (3 mg/kg) dosed every 2 weeks. Dose-limiting toxicities were evaluated in the first 28 days of treatment. Neoantigen burden was assessed from pre-treatment tumor biopsy, as available, by next-generation sequencing. Fcγ receptor genotyping was assessed by real-time PCR. Immunophenotyping of peripheral blood mononuclear cells collected pre- and post-treatment were analyzed by flow cytometry.ResultsPreclinically, AGEN1181 demonstrated superior T cell activation than a standard IgG1 anti-CTLA-4 analogue in donors expressing either the low or high affinity FcγRIIIA. In poorly immunogenic tumor-bearing mouse models, AGEN1181-like surrogate demonstrated robust tumor control in combination with anti-PD-1 and focal radiation or chemotherapy. As of August 25th, 2020, we observed a clinical benefit rate of 63–53% at 6 and 12 weeks respectively among evaluable treated patients. We observed two durable responses in patients with endometrial cancer that were BRCA-, microsatellite stable and PD-L1 negative. These patients progressed on prior PD-1 therapy or chemoradiation respectively. Notably, responders expressed either the low or high affinity FcγRIIIA. AGEN1181 showed potent dose-dependent increases in peripheral CD4+Ki67+, CD4+ICOS+ and CD4+HLA-DR+ T-cells. Treatment was well tolerated through the highest dose tested. Grade 3 or greater immune-related adverse events occurred in 28.5% patients and were consistent with CTLA-4 therapies.ConclusionsAGEN1181 is designed to expand the benefit of anti-CTLA-4 therapy to a broader patient population. AGEN1181, alone or in combination with balstilimab, demonstrates clinical activity in heavily pretreated patients.Trial RegistrationNCT03860272

613 HER2-XPAT, a novel protease-activatable prodrug T cell engager (TCE), with potent T-cell activation and efficacy in solid tumors and large predicted safety margins in non-human primate (NHP)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A649-A649
Author(s):  
Fiore Cattaruzza ◽  
Ayesha Nazeer ◽  
Zachary Lange ◽  
Caitlin Koski ◽  
Mikhail Hammond ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytokine Production ◽  
Antigenic Specificity ◽  
The Core ◽  
Protease Cleavage ◽  
Safety Margins

BackgroundTCEs are effective in leukemias but have been challenging in solid tumors due to on-target, off-tumor toxicity. Attempts to circumvent CRS include step-up dosing and/or complex designs but are unsuccessful due to toxicity and/or enhanced immunogenicity. HER2-XPAT, or XTENylated Protease-Activated bispecific T-Cell Engager, is a prodrug TCE that exploits the protease activity present in tumors vs. healthy tissue to expand the therapeutic index (TI). The core of the HER2-XPAT (PAT) consists of 2 tandem scFvs targeting CD3 and HER2. Attached to the core, two unstructured polypeptide masks (XTEN) sterically reduce target engagement and extend T1/2. Protease cleavage sites at the base of the XTEN masks enable proteolytic activation of XPATs in the tumor microenvironment, unleashing a potent TCE with short T1/2, further improving the TI. HER2-XPAT, a tumor protease-activatable prodrug with wide safety margins, can co-opt T-cells regardless of antigenic specificity to induce T-cell killing of HER2+ tumors.MethodsPreclinical studies were conducted to characterize the activity of HER2-XPAT, HER2-PAT (cleaved XPAT), and HER2-NonClv (a non-cleavable XPAT) for cytotoxicity in vitro, for anti-tumor efficacy in xenograft models, and for safety in NHPs.ResultsHER2-PAT demonstrated potent in vitro T-cell cytotoxicity (EC50 1-2pM) and target-dependent T-cell activation and cytokine production by hPBMCs. HER2-XPAT provided up to 14,000-fold protection against killing of HER2 tumor cells and no cytotoxicity against cardiomyocytes up to 1uM. In vivo, HER2-XPAT induced complete tumor regressions in BT-474 tumors with equimolar dosing to HER2-PAT, whereas HER2-NonClv had no efficacy, supporting requirement of protease cleavage for T-cell activity. In NHP, HER2-XPAT has been dose-escalated safely up to 42mg/kg (MTD). HER2-XPAT demonstrated early T-cell margination at 2 mg/kg but largely spared CRS, cytokine production, and tissue toxicity up to 42 mg/kg. PK profiles of HER2-XPAT and HER2-NonClv were comparable, consistent with ex vivo stability for cleavage when incubated in cancer pts plasma for 7 days at 37°C. HER2-PAT by continuous infusion induced lethal CRS and cytokine spikes at 0.3 mg/kg/d but was tolerated at 0.25 mg/kg/d, providing HER2-XPAT with >1300-fold protection in tolerability vs. HER2-PAT, >4 logs over cytotoxicity EC50s for HER2 cell lines, and a 20-fold safety margin over the dose required for pharmacodynamic activity.ConclusionsHER2-XPAT is a potent prodrug TCE with no CRS and a wide TI based on NHPs. With XTEN’s clinical data demonstrating low immunogenicity, the XPATs are a promising solution. IND studies are ongoing. Additional PK/PD, cytokines, safety, and efficacy data will be presented.

scholarly journals In Vitro Evaluation of CD276-CAR NK-92 Functionality, Migration and Invasion Potential in the Presence of Immune Inhibitory Factors of the Tumor Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1020
Author(s):  
Stefan Grote ◽  
Guillermo Ureña-Bailén ◽  
Kenneth Chun-Ho Chan ◽  
Caroline Baden ◽  
Markus Mezger ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Immune Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Migration And Invasion ◽  
Cellular Immunotherapy ◽  
Knock Out ◽  
Immunosuppressive Tumor Microenvironment

Background: Melanoma is the most lethal of all skin-related cancers with incidences continuously rising. Novel therapeutic approaches are urgently needed, especially for the treatment of metastasizing or therapy-resistant melanoma. CAR-modified immune cells have shown excellent results in treating hematological malignancies and might represent a new treatment strategy for refractory melanoma. However, solid tumors pose some obstacles for cellular immunotherapy, including the identification of tumor-specific target antigens, insufficient homing and infiltration of immune cells as well as immune cell dysfunction in the immunosuppressive tumor microenvironment (TME). Methods: In order to investigate whether CAR NK cell-based immunotherapy can overcome the obstacles posed by the TME in melanoma, we generated CAR NK-92 cells targeting CD276 (B7-H3) which is abundantly expressed in solid tumors, including melanoma, and tested their effectivity in vitro in the presence of low pH, hypoxia and other known factors of the TME influencing anti-tumor responses. Moreover, the CRISPR/Cas9-induced disruption of the inhibitory receptor NKG2A was assessed for its potential enhancement of NK-92-mediated anti-tumor activity. Results: CD276-CAR NK-92 cells induced specific cytolysis of melanoma cell lines while being able to overcome a variety of the immunosuppressive effects normally exerted by the TME. NKG2A knock-out did not further improve CAR NK-92 cell-mediated cytotoxicity. Conclusions: The strong cytotoxic effect of a CD276-specific CAR in combination with an “off-the-shelf” NK-92 cell line not being impaired by some of the most prominent negative factors of the TME make CD276-CAR NK-92 cells a promising cellular product for the treatment of melanoma and beyond.

Altered immune cell profiles and impaired CD4 T cell activation in single and multi‐food allergic adolescents

2021 ◽  
Author(s):  
Melanie R. Neeland ◽  
Sandra Andorf ◽  
Thanh D. Dang ◽  
Vicki L. McWilliam ◽  
Kirsten P. Perrett ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Cd4 T Cell

Abstract 095: CD74 Deficient Mice are Resistant to Toll-Like Receptor-Induced Preeclampsia

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Mohamad Hatahet ◽  
Olga Y Gasheva ◽  
Valorie L Chiasson ◽  
Piyali Chatterjee ◽  
Kelsey R Bounds ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Endothelial Dysfunction ◽  
Mhc Class Ii ◽  
Immune Cells ◽  
Immune Cell ◽  
Class Ii ◽  
Poly I:C ◽  
Hypertensive Disorder ◽  
Toll Like Receptor

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by vascular endothelial dysfunction and excessive immunity and inflammation. Activation of the dsRNA receptor Toll-like receptor 3 (TLR3) or the ssRNA receptor TLR7 elicits a pregnancy-dependent PE-like syndrome in mice by inducing a pro-inflammatory immune response. CD74 (MHC Class II invariant chain) acts as a chaperone for MHC Class II surface expression on immune cells during antigen presentation and is cleaved into Class II-Associated Invariant Peptide (CLIP) following polyclonal activation of immune cell TLRs. The presence of CLIP in the groove of MHC Class II prevents T cell-dependent death leading to persistent immune cell activation. We hypothesized that genetic deletion of CD74 and subsequent depletion of CLIP on immune cells prevents TLR-induced immune responses and the development of PE in mice. Pregnant WT and CD74 KO mice were given i.p. injections of normal saline (P), poly I:C (TLR3 agonist; P-PIC), or R837 (TLR7 agonist; P-R837) on gestational days 13, 15, and 17 and euthanized on day 18. P-PIC and P-R837 WT mice had significantly increased splenic levels of pro-inflammatory CD3+/gd T cells and plasma levels of the gd T cell-derived cytokines IFNg, TNFa, and IL-17 compared to P WT mice whereas P-PIC and P-R837 CD74 KO mice had significantly increased anti-inflammatory CD3+/gd T cells and no significant increases in plasma IFNg, TNFa, and IL-17 levels. P-PIC and P-R837 CD74 KO mice did not develop the hypertension (gd17 SBP in mmHg: P WT=102±3, P CD74 KO=100±3, P-PIC WT=147±4*, P-PIC CD74 KO=95±3, P-R837 WT=133±2*, P-R837 CD74 KO=97±1; *p<0.05 vs. P WT), endothelial dysfunction, proteinuria, or placental necrosis seen in P-PIC and P-R837 WT mice. In conclusion, CD74 is crucial for the development of TLR-induced PE-like symptoms in mice and CD74/CLIP depletion may be a promising therapeutic target for women with PE.

Single Cell Profiling Reveals Unique CXCL13 Positive T Cell Subsets in the Tumor Microenvironment of Lymphocyte Rich Classic Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Tomohiro Aoki ◽  
Lauren C. Chong ◽  
Katsuyoshi Takata ◽  
Katy Milne ◽  
Elizabeth Chavez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Single Cell ◽  
Immune Cells ◽  
Research Funding ◽  
Immune Cell ◽  
Expression Patterns ◽  
The Other ◽  
Tfh Cells

Introduction: Classic Hodgkin lymphoma (CHL) features a unique crosstalk between malignant cells and different types of normal immune cells in the tumor-microenvironment (TME). On the basis of histomorphologic and immunophenotypic features of the malignant Hodgkin and Reed-Sternberg (HRS) cells and infiltrating immune cells, four histological subtypes of CHL are recognized: Nodular sclerosing (NS), Mixed cellularity, Lymphocyte-rich (LR) and Lymphocyte-depleted CHL. Recently, our group described the high abundance of various types of immunosuppressive CD4+ T cells including LAG3+ and/or CTLA4+ cells in the TME of CHL using single cell RNA sequencing (scRNAseq). However, the TME of LR-CHL has not been well characterized due to the rarity of the disease. In this study, we aimed at characterizing the immune cell profile of LR-CHL at single cell resolution. METHODS: We performed scRNAseq on cell suspensions collected from lymph nodes of 28 primary CHL patients, including 11 NS, 9 MC and 8 LR samples, with 5 reactive lymph nodes (RLN) serving as normal controls. We merged the expression data from all cells (CHL and RLN) and performed batch correction and normalization. We also performed single- and multi-color immunohistochemistry (IHC) on tissue microarray (TMA) slides from the same patients. In addition, an independent validation cohort of 31 pre-treatment LR-CHL samples assembled on a TMA, were also evaluated by IHC. Results: A total of 23 phenotypic cell clusters were identified using unsupervised clustering (PhenoGraph). We assigned each cluster to a cell type based on the expression of genes described in published transcriptome data of sorted immune cells and known canonical markers. While most immune cell phenotypes were present in all pathological subtypes, we observed a lower abundance of regulatory T cells (Tregs) in LR-CHL in comparison to the other CHL subtypes. Conversely, we found that B cells were enriched in LR-CHL when compared to the other subtypes and specifically, all four naïve B-cell clusters were quantitatively dominated by cells derived from the LR-CHL samples. T follicular helper (TFH) cells support antibody response and differentiation of B cells. Our data show the preferential enrichment of TFH in LR-CHL as compared to other CHL subtypes, but TFH cells were still less frequent compared to RLN. Of note, Chemokine C-X-C motif ligand 13 (CXCL13) was identified as the most up-regulated gene in LR compared to RLN. CXCL13, which is a ligand of C-X-C motif receptor 5 (CXCR5) is well known as a B-cell attractant via the CXCR5-CXCL13 axis. Analyzing co-expression patterns on the single cell level revealed that the majority of CXCL13+ T cells co-expressed PD-1 and ICOS, which is known as a universal TFH marker, but co-expression of CXCR5, another common TFH marker, was variable. Notably, classical TFH cells co-expressing CXCR5 and PD-1 were significantly enriched in RLN, whereas PD-1+ CXCL13+ CXCR5- CD4+ T cells were significantly enriched in LR-CHL. These co-expression patterns were validated using flow cytometry. Moreover, the expression of CXCR5 on naïve B cells in the TME was increased in LR-CHL compared to the other CHL subtypes We next sought to understand the spatial relationship between CXCL13+ T cells and malignant HRS cells. IHC of all cases revealed that CXCL13+ T cells were significantly enriched in the LR-CHL TME compared to other subtypes of CHL, and 46% of the LR-CHL cases showed CXCL13+ T cell rosettes closely surrounding HRS cells. Since PD-1+ T cell rosettes are known as a specific feature of LR-CHL, we confirmed co-expression of PD-1 in the rosetting cells by IHC in these cases. Conclusions: Our results reveal a unique TME composition in LR-CHL. LR-CHL seems to be distinctly characterized among the CHL subtypes by enrichment of CXCR5+ naïve B cells and CD4+ CXCL13+ PD-1+ T cells, indicating the importance of the CXCR5-CXCL13 axis in the pathogenesis of LR-CHL. Figure Disclosures Savage: BeiGene: Other: Steering Committee; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Scott:Janssen: Consultancy, Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy. Steidl:AbbVie: Consultancy; Roche: Consultancy; Curis Inc: Consultancy; Juno Therapeutics: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding.

scholarly journals Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5856
Author(s):  
Myung-Chul Kim ◽  
Zeng Jin ◽  
Ryan Kolb ◽  
Nicholas Borcherding ◽  
Jonathan Alexander Chatzkel ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Single Cell Analysis ◽  
Clear Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Cellular Mechanisms ◽  
T Cell Infiltration ◽  
Immunological Mechanisms

Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.

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