Inducible T-cell Costimulator Expression Research Articles

ICOS agonist vopratelimab modulates follicular helper T cells and improves B cell function in common variable immunodeficiency

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (TFH) play a central role in humoral immunity, we examined TFH cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate TFH, B cell interactions and enhance immunoglobulin production. CVID subjects had decreased TFH17 and increased TFH1 subsets; this was associated with increased transitional B cells and decreased IgG+ B and IgD−IgM−CD27+ memory B cells. ICOS expression on CVID CD4+ T cells was also decreased. However, ICOS activation of CD4+ T cells by vopratelimab significantly increased total CVID TFH, TFH2, cell numbers, as well as IL-4, IL-10 and IL-21 secretion in vitro. Vopratelimab treatment also increased plasma cells, IgG+ B cells, reduced naïve & transitional B cells and significantly increased IgG1 secretion by CVID B cells. Interestingly, vopratelimab treatment also restored IgA secretion in PBMCs from several CVID patients who had a complete lack of endogenous serum IgA. Our data demonstrate the potential of TFH modulation in restoring TFH and enhancing B cell maturation in CVID. The effects of an ICOS agonist in antibody defects warrants further investigation. This biologic may also be of therapeutic interest in other clinical settings of antibody deficiency.

Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development

Fine-mapping and functional studies implicate rs117701653, a non-coding single nucleotide polymorphism in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis and type 1 diabetes. Here, using DNA pulldown, mass spectrometry, genome editing and eQTL analysis, we establish that the disease-associated risk allele is functional, reducing affinity for the inhibitory chromosomal regulator SMCHD1 to enhance expression of inducible T-cell costimulator (ICOS) in memory CD4+ T cells from healthy donors. Higher ICOS expression is paralleled by an increase in circulating T peripheral helper (Tph) cells and, in rheumatoid arthritis patients, of blood and joint fluid Tph cells as well as circulating plasmablasts. Correspondingly, ICOS ligation and carriage of the rs117701653 risk allele accelerate T cell differentiation into CXCR5-PD-1high Tph cells producing IL-21 and CXCL13. Thus, mechanistic dissection of a functional non-coding variant in human autoimmunity discloses a previously undefined pathway through which ICOS regulates Tph development and abundance.

Molecular and clinical characterization of ICOS expression in breast cancer through large-scale transcriptome data.

ICOS (Inducible T Cell Costimulator), one of the co-stimulatory B7 superfamily members, was characterized as a co-stimulatory receptor for T-cell enhancement. However, the role of ICOS in breast cancer remains largely unknown. The present study systematically investigated the expression pattern and its relation to clinical characteristics and immunotherapy by integrating multiple clinical cohorts and large-scale gene expression data. This study included 2994 breast tumor samples with transcriptome data and matched clinical data. To make our findings more reliable, we set the TCGA cohort as the discovery set and the METABRIC cohort as the validation set. The expression of ICOS in breast cancer is strongly associated with major clinical and molecular characteristics. There is an association between higher ICOS expression and malignant subtypes and grades of tumors. In addition, gene ontology analysis based on genes significantly correlated with ICOS expression indicated that the expression of ICOS is mainly associated with immune responses and inflammation. We also observed strong correlations between ICOS and other promising immune-checkpoint molecules, including PD1, PDL1, CTLA4, and IDO1. Furthermore, we found that ICOS expression is associated with the response to anti-PDL1 immunotherapy and may serve as a biomarker for immunotherapy prediction. Our results indicated higher ICOS expression is significantly associated with favorable survival in triple-negative breast cancer (TNBC) patients, but not for all subtypes of breast cancer patients. In summary, ICOS correlates with higher malignant breast cancers, and it contributes to the regulation of the immune microenvironment of breast tumors, making it a potential biomarker and immunotherapy target.

Reciprocal costimulatory molecules control the activation of mucosal type 3 innate lymphoid cells during engagement with B cells

Innate lymphoid cells (ILCs) are the counterpart of T helper cells in the innate immune system and share multiple phenotypes with T helper cells. Inducible T-cell costimulator (ICOS) is recognized on T cells and participates in T-cell activation and T and B-cell engagement in lymphoid tissues. However, the role of ICOS in ILC3s and ILC3-involved interactions with the immune microenvironment remains unclear. Here, we found that ICOS expression on human ILC3s was correlated with the activated state of ILC3s. ICOS costimulation enhanced the survival, proliferation, and capacity of ILC3s to produce cytokines (IL-22, IL-17A, IFN-γ, TNF, and GM-CSF). Via synergistic effects of ICOS and CD40 signaling, B cells promoted ILC3 functions, and ILC3-induced T-cell-independent B-cell IgA and IgM secretion primarily required CD40 signaling. Hence, ICOS is essential for the nonredundant role of ILC3s and their interaction with adjacent B cells.

ICOS/ICOSLG and PD-1 Co-Expression is Associated with the Progression of Colorectal Precancerous- Carcinoma Immune Microenvironment.

This study aimed to investigate the expression of inducible T-cell co-stimulator (ICOS) and its ligand (ICOSLG), along with their association with clinicopathological features and influence on the immune profile in colorectal cancer (CRC). The Cancer Genome Atlas Colorectal Adenocarcinoma cohorts were used. We also analyzed 131 clinical samples of colon lesions, including precancerous lesions (hyperplastic polyps, low-grade dysplasia, and high-grade dysplasia) and CRC tissues. We conducted immunohistochemical (IHC) assays and multiple IHC (mIHC) of CD4+, Foxp3+ tumor-infiltrating lymphocytes (TILs), and PD-1/PD-L1 immune checkpoints in precancerous lesions and CRC samples from our patient subsets to determine changes and correlations in ICOS and ICOSLG expression during progression through the adenoma-carcinoma pathway. High expression of ICOS and ICOSLG was a significant factor in CRC in multiple analyses and was positively correlated with CD4+/Foxp3+ TIL density and PD-1/PD-L1 expression, which increased with the sequential progression of lesions from precancerous tissues to carcinoma. Multivariable logistic regression analysis suggested that the location and expression level of ICOS/ICOSLG may be involved in precancerous-carcinoma progression. The co-expression status of PD-1 and ICOS/ ICOSLG could stratify patients with colorectal lesions into three groups of low, moderate, and high risk of progression. According to this classification and mIHC assays, we found a strong correlation between increased PD-1+ICOS+ or PD-1+ICOSLG+ co-expression and CRC, which might be deemed an independent factor in carcinogenesis. Increased ICOS/ICOSLG expression may be associated with the progressive formation of Foxp3+ TILs in the immune microenvironment and may further promote the development of the abnormal cytology of colorectal lesions from precancerous neoplasia to CRC. Our findings support the interpretation that enhanced co-expression of PD-1+ICOS+ or PD-1+ICOSLG+ contributes to the immune-active microenvironment of the colorectal adenoma-carcinoma sequence.

Expression of ICOS in the salivary glands of patients with primary Sjogren's syndrome and its molecular mechanism.

The present study aimed to explore latent markers for identifying primary Sjogren's syndrome (pSS), as well as their expression and molecular mechanism. Hub inducible T cell co-stimulator genes were retrieved from the Gene Expression Omnibus. A total of 95 patients with pSS and 68 healthy individuals from Affiliated Hospital of Nantong University (Nantong, China) were included in the study. The expression of inducible T cell co-stimulator (ICOS) in whole blood and saliva was evaluated using ELISA. Western blotting was performed to investigate aquaporin 5 (AQP5) protein expression, as well as the inflammatory effects of ICOS in patients with pSS compared with healthy individuals. Differentially expressed mRNAs were analyzed in whole blood (GSE84844) and salivary gland (GSE40611) of patients with pSS. In total, 15 hub genes were identified, among which ICOS was indicated to serve a role in the most pivotal immunity pathways. pSS was markedly associated with inflammatory pathways. Results from the present study found that ICOS was upregulated in the salivary gland, whole blood and saliva of patients with pSS. Salivary weight was negatively correlated with the levels of ICOS in the saliva of patients with pSS. The expression of AQP5 was markedly lower in patients with pSS. The expression of AQP5 was negatively associated with ICOS. Compared with that of healthy individuals, the expression of ICOS and inflammatory factors was higher and the expression of AQP5 was lower in pSS patients as assessed by western blotting. These data demonstrated that ICOS may affect AQP5 expression by promoting inflammation in the salivary glands of patients with pSS.

Tph Cells Expanded in Primary Sjögren's Syndrome.

ObjectivesPD-1+CXCR5–CD4+T peripheral helper cells, named Tph cells, contribute to B-cell immune responses and the production of antibodies in systemic lupus erythematosus and rheumatoid arthritis. However, the role of Tph cells was unknown in the pathogenesis of primary Sjögren’s syndrome (pSS). Here, we aim to explore the contribution of Tph cells in the development of pSS.MethodsSixty patients with pSS and 61 age and sex-matched healthy individuals were recruited for this study. The frequency of Tph cells in the blood was measured by flow cytometry. The expression of inducible T-cell costimulator (ICOS), MHC-II, IL-21, CCR2, CCR5, and CCR9 was evaluated in Tph cells. The relationship between Tph cells and indicators of clinical disease was assessed. Co-expression levels of PD-1, CXCR5, CD4, CCR2, and CCR5 in the salivary gland specimens from patients with pSS and patients with dry mouth and eyes but normal pathology were also analyzed.ResultsWe demonstrated increased circulating Tph cells (7.53 ± 6.65% vs. 3.08 ± 1.31%, p < 0.0001) in patients with pSS (n = 60) compared to healthy controls (n = 61). Tph cells were significantly associated with the ESSDAI disease activity scores, IgG, ESR, IL-21, anti-SSA antibody, and CD138+/CD19+ plasma cells. Furthermore, ICOS was highly expressed in Tfh and Tph cells in patients with pSS. IL-21, MHC-II, CCR2, and CCR5 expression was higher in pSS Tph cells, and CCR9 expression was lower in pSS Tph cells than in pSS Tfh cells. Moreover, Tph cells and CCR2+CD4+T and CCR5+CD4+T cells were found in the labial gland of patients with pSS.ConclusionOur data show that Tph cells were enriched in peripheral blood and labial gland of patients with pSS. Circulating Tph cells correlated with disease activity scores, suggesting a crucial role of Tph in the development of pSS.

Expression of immune checkpoint molecules programmed death protein 1, programmed death-ligand 1 and inducible T-cell co-stimulator in mycosis fungoides and Sézary syndrome: association with disease stage and clinical outcome.

BackgroundThe relationship between immune checkpoint status and disease outcome is a major focus of research in cutaneous T‐cell lymphoma (CTCL), a disfiguring neoplastic dermatological disorder. Mycosis fungoides (MF) and Sézary syndrome (SS) are the two most common types of CTCL.ObjectivesThe aim was to evaluate the immune checkpoint markers programmed death protein 1 (PD1), inducible T‐cell co‐stimulator (ICOS) and programmed death‐ligand 1 (PD‐L1) in skin biopsies from patients with CTCL relative to disease stage and overall survival.MethodsThis consecutive case series enrolled 47 patients: 57% had stage IA–IIA disease and 43% had stage IIB–IVA2 disease (including seven with SS).ResultsPD1, PD‐L1 and ICOS expression was seen in all biopsies. Notably, PD‐L1 was predominantly expressed on histiocytes/macrophages, but focal expression on CTCL cells was seen. High expression of either ICOS or PD‐L1 was associated with advanced‐stage disease (P = 0·007 for both) and with the appearance of large‐cell transformation (LCT), a histopathological feature associated with a poor prognosis (ICOS: P = 0·02; PD‐L1: P = 0·002). PD1 expression was not significantly associated with disease stage (P = 0·12) or LCT (P = 0·49), but expression was high in SS biopsies. A high combined checkpoint marker score (PD1, PD‐L1 and ICOS) was associated with advanced‐stage disease (P = 0·001), LCT (P = 0·021) and lower overall survival (P = 0·014).ConclusionsThese findings demonstrate the existence of a complex immunoregulatory microenvironment in CTCL and support the development of immunotherapies targeting ICOS and PD‐L1 in advanced disease.

The ICOS-ICOSL pathway tunes thymic selection.

Negative selection of developing T cells plays a significant role in T‐cell tolerance to self‐antigen. This process relies on thymic antigen‐presenting cells which express both self‐antigens and cosignaling molecules. Inducible T‐cell costimulator (ICOS) belongs to the CD28 family of cosignaling molecules and binds to ICOS ligand (ICOSL). The ICOS signaling pathway plays important roles in shaping the immune response to infections, but its role in central tolerance is less well understood. Here we show that ICOSL is expressed by subsets of thymic dendritic cells and medullary thymic epithelial cells as well as thymic B cells. ICOS expression is upregulated as T cells mature in the thymus and correlates with T‐cell receptor signal strength during thymic selection. We also provide evidence of a role for ICOS signaling in mediating negative selection. Our findings suggest that ICOS may fine‐tune T‐cell receptor signals during thymic selection contributing to the generation of a tolerant T‐cell population.

ICOS Expression Is Required for Maintenance but Not the Formation of Germinal Centers in the Spleen in Response to Plasmodium yoelii Infection.

Inducible T cell costimulator (ICOS) plays a key role in the differentiation and maintenance of follicular helper T (Tfh) cells and, thus, germinal center (GC) formation. Previously, our laboratory showed in a Plasmodium chabaudi infection model that Icos-/- mice were significantly impaired in their ability to form GCs despite persistent infection and, thus, a continued antigen (Ag) load. Here, we show that the resolution of primary infection with Plasmodium yoelii was delayed in Icos-/- mice. This phenotype was associated with a reduction in the accumulation of Tfh-like and GC Tfh cells and an early deficiency in Ag-specific antibody (Ab) production. However, Icos-/- mice could form GCs, although they were less frequent in number than in wild-type (WT) mice. Nonetheless, the Ag-specific Abs from Icos-/- mice lacked signs of affinity maturation, suggesting functional defects associated with these GCs. Eventually, these GC structures dissipated more rapidly in Icos-/- mice than in WT mice. Moreover, the ability of Icos-/- mice to form these GC structures is not reliant on the high Ag loads associated with P. yoelii infections, as GC formation was preserved in Icos-/- mice treated with atovaquone. Finally, mice were unable to form secondary GCs in the absence of ICOS after rechallenge. Overall, these data demonstrate the necessity of ICOS in the maintenance of Tfh cells, the formation and maintenance of sufficient numbers of functioning GCs, and the ability to generate new GC structures after reinfection with P. yoelii.

37P Prognostic significance of immune checkpoint molecule expression in resectable gastric adenocarcinoma

Survival rates of gastric cancer remain poor and, hence, there is a great need to identify novel treatment strategies and relevant predictive and prognostic biomarkers. Immunotherapies targeting the PD-1/PD-L1 checkpoints have shown promising results, but simultaneous inhibition of other immune checkpoint molecules may further improve clinical outcome. The expression and prognostic significance of other immune checkpoint molecules have not been extensively explored, especially among resectable gastric cancer patients. Herein, we prospectively examined the expression of several immune checkpoints and their correlation with survival in patients with resectable gastric cancer. 39 patients who underwent curative surgery for gastric adenocarcinoma at Fundeni Clinical Institute were included in this study. The expression patterns of several immune checkpoints with either co-stimulatory, such as CD28, inducible T-cell CO-Stimulator (ICOS), CD27, glucocorticoid-induced tumor necrosis factor receptor (GITR), or co-inhibitory activity, including PD-1, CTLA4, BTLA, lymphocyte-activation gene 3 (LAG3), TIM3 and IDO, were examined on immune cells using Luminex xMAP technology with ProcartaPlex Human Immuno-Oncology Checkpoint Marker panel 14-plex from tumoral and peritumoral resected specimens. Increased LAG-3 and GITR expression in primary tumors were independent factors for prolonged overall survival (p=0.02 and p=0.008, respectively). Conversely, ICOS was associated with shorter overall survival (p=0.04). Moreover, ICOS expression in primary tumors was significantly associated with PD-1 expression while GITR expression was positively correlated with TIM-3. No statistically significant association was found between the other immune checkpoint molecules and survival. Our results indicate that increased expression levels of LAG-3, GITS and ICOS are independent prognostic factors for overall survival in patients with curatively resected gastric cancer. These immune checkpoint molecules should be further evaluated as novel predictive and/or therapeutic targets for gastric cancer patients.

Impact of HIV-1 Infection and Antigen Class on T Follicular Helper Cell Responses to Pneumococcal Polysaccharide-Protein Conjugate Vaccine-13.

Pneumococcal infections are common and serious complications of HIV-1 disease. Prevention has been compromised by the limited magnitude and quality of Ab responses to T cell-independent type 2 pneumococcal capsular polysaccharides (PPS). The pneumococcal polysaccharide-protein conjugate vaccine-13 (PCV-13) contains PPS conjugated to the T cell-dependent protein (diphtheria toxoid [DT] [CRM197]). We investigated the differential response to PPS and DT by human Ab-secreting B cells (ASC) after immunization with PCV-13 in newly diagnosed healthy HIV+ and control adults. The numbers of PPS-specific IgG ASC increased significantly and similarly in HIV+ and controls. However, DT-specific IgG ASC increased in controls but not HIV+ subjects. To determine the cellular basis of these disparate responses to DT and PPS, we characterized the frequency and activation of T follicular helper (Tfh) cells, the predominant T cell subset providing B cell help. Expression of inducible T cell costimulator (ICOS), which sustains Tfh function and phenotype, increased significantly among controls, when compared with the HIV+ group. Increases in ICOS+ Tfh correlated with changes in T-dependent, DT-specific IgG ASC in controls but not in HIV+ In contrast, ICOS expression did not correlate with T cell-independent type 2 PPS-specific ASC in either group. Of note, upon optimized ex vivo stimulation, CD4 T cells from HIV+ subjects differentiated into Tfh cells and formed synapses with Raji B cells at frequencies similar to that of controls. In summary, PCV-13-induced increase in ICOS expression on Tfh was associated with responses to DT, which was compromised in recently diagnosed healthy HIV+ adults and can be restored ex vivo by providing effective Tfh-differentiating signals.

Increased circulating PD-1hiCXCR5- peripheral helper T cells are associated with disease severity of active ulcerative colitis patients

PurposeA recently identified population of T cells, phenotypically CD4+PD-1hiCXCR5−, has been firstly termed as peripheral helper T cells (Tph) and found to be pathogenic in autoimmune diseases. However, the potential role of Tph in ulcerative colitis (UC) remains unclear. We aim to investigate the changes of circulating Tph in UC patients and their potential significance in the pathogenesis of UC. MethodsTotally 68 UC patients and 34 age- and sex-matched healthy controls were enrolled. Circulating Tph and B cell subsets were analyzed by flow cytometry. Expressions of inducible T-cell co-stimulator (ICOS) on Tph cells were analyzed. Serum IL-4, IL-10, IL-12 and IL-21 were detected using ELISA. Correlation analyses were conducted between Tph cells and disease severity, functional B cell subsets and serum cytokines. ResultsBoth the frequency and absolute number of Tph were significantly increased in active UC patients and ICOS levels in Tph cells were also elevated, compared with remission UC patients and healthy controls. Tph and ICOS expression were significantly positively correlated with Mayo score and serum CRP in active UC patients, and were significantly decreased when achieving remission after treatment. Tph levels were correlated with new memory B cells, plasmablasts, serum IL-4 and IL-21. Meanwhile, serum IL-10 showed negative correlation while IL-12 exhibited positive correlation with circulating Tph cells in UC patients. ConclusionsCirculating Tph cells are elevated in active UC patients and are associated with the disease activity, which may contribute to the pathogenesis of UC.

Immune Skew of Circulating Follicular Helper T Cells Associates With Myasthenia Gravis Severity.

ObjectiveTo clarify functional alterations of follicular helper T cells (Tfh) in myasthenia gravis (MG) because Tfh play important roles in helping B cells generate antibody-producing cells.MethodsA total of 24 immunotherapy-naive patients with anti–acetylcholine receptor (AchR) antibody–positive MG and 18 age-matched healthy subjects (HS) were enrolled. Samples from 6 patients were available for posttreatment analysis. Subsets of circulating Tfh (cTfh) and B cells were identified by flow cytometry analysis of surface molecules. Cytokine production by isolated cTfh subsets from 5 patients with MG and 5 HS was measured in vitro. Analysis was performed to examine the correlation between the frequency of cTfh subsets and that of plasmablasts and between cTfh subsets and the quantitative MG score.ResultscTfh increased with elevated expression of inducible T-cell costimulator (ICOS) in patients with MG. cTfh shifted to Th2 and Th17 over Th1 in MG. ICOShighcTfh produced significantly higher levels of interleukin (IL)-21, IL-4, and IL-17A than ICOSlow cTfh only in patients with MG. The frequency of cTfh within CD4 T cells was more closely associated with disease severity than the serum anti-AchR antibody titer and frequency of plasmablasts within B cells. Abnormalities of cTfh were improved after immunotherapy in parallel with clinical improvement.ConclusionsAlternation of cTfh is a key feature in the development of MG and may become a biomarker for disease severity and therapeutic efficacy.Classification of EvidenceThis study provides Class II evidence that the level of cTfh is associated with disease severity in patients with MG.

ImmunoPET: Development of a Radiotracer to Monitor Inducible T-cell Costimulator Expression in Response to Immunotherapy.

ImmunoPET: Development of a Radiotracer to Monitor Inducible T-cell Costimulator Expression in Response to Immunotherapy.

ICOS Is an Indicator of T-cell-Mediated Response to Cancer Immunotherapy.

Immunotherapy is innovating clinical cancer management. Nevertheless, only a small fraction of patient's benefit from current immunotherapies. To improve clinical management of cancer immunotherapy, it is critical to develop strategies for response monitoring and prediction. In this study, we describe inducible T-cell costimulator (ICOS) as a conserved mediator of immune response across multiple therapy strategies. ICOS expression was evaluated by flow cytometry, 89Zr-DFO-ICOS mAb PET/CT imaging was performed on Lewis lung cancer models treated with different immunotherapy strategies, and the change in tumor volume was used as a read-out for therapeutic response. ImmunoPET imaging of ICOS enabled sensitive and specific detection of activated T cells and early benchmarking of immune response. A STING (stimulator of interferon genes) agonist was identified as a promising therapeutic approach in this manner. The STING agonist generated significantly stronger immune responses as measured by ICOS ImmunoPET and delayed tumor growth compared with programmed death-1 checkpoint blockade. More importantly, ICOS ImmunoPET enabled early and robust prediction of therapeutic response across multiple treatment regimens. These data show that ICOS is an indicator of T-cell-mediated immune response and suggests ICOS ImmunoPET as a promising strategy for monitoring, comparing, and predicting immunotherapy success in cancer. SIGNIFICANCE: ICOS ImmunoPET is a promising strategy to noninvasively predict and monitor immunotherapy response.See related commentary by Choyke, p. 2975.

Blockade of CTLA-4 and PD-1 Enhances Adoptive T-cell Therapy Efficacy in an ICOS-Mediated Manner.

Adoptive transfer of tumor-reactive T cells (ACT) has led to modest clinical benefit in the treatment of solid tumors. Failures with this therapy are primarily due to inadequate infiltration and poor function of adoptively transferred cells in the tumor microenvironment. To improve the efficacy of ACT, we combined ACT with dual blockade of CTLA-4 and PD-1. Treatment with anti-CTLA-4 plus anti-PD-1 compared with monotherapy resulted in durable antitumor responses, enhanced effector function of ACT, utilizing PMEL-1 transgenic (Tg+) CD8+ T cells, and improved survival. Using PMEL-1ICOS-/- mice, we showed that deletion of the inducible T-cell costimulator (ICOS) receptor abolished the therapeutic benefits, with selective downregulation of Eomesodermin (Eomes), interferon gamma (IFNγ), and perforin. Higher expression of IFNγ and Eomes was noted in human ICOShi CD8+ T cells compared with ICOSlow counterparts. Together, our data provide direct evidence that ACT combined with immune-checkpoint therapy confers durable antitumor responses, which largely depended on CD8+ T-cell-intrinsic expression of ICOS. Our study provides a foundation of testing combinatorial therapy of ACT of CD8 T cells and dual blocking of CTLA-4 and PD-1 in patients with melanoma.

1468P - Effector CD4+ T-cell induction by thoracic radiotherapy for patients with NSCLC

BackgroundA recent clinical study indicated that anti-programmed death-ligand 1 antibody durvalumab consolidation therapy for patients with non-small cell lung cancer (NSCLC) who received chemoradiotherapy (CRT) resulted in robust improvement in progression-free survival (PFS) and prevented distant metastasis. It has been demonstrated that cluster of differentiation (CD)8+ T cell priming is facilitated by immunogenic cancer cell death by radiotherapy. On the other hand, accumulating evidence indicates that CD4+ T cells are required for effective antitumor T cell responses because CD4+ T cells help regulate priming, migration, invasive potential, and antitumor killing activity of cytotoxic lymphocytes. It remains uncertain how thoracic CRT evokes antitumor T cell immune responses in patients with NSCLC. MethodsThe present study comprised 56 consecutive patients with locally advanced NSCLC who received curative CRT or thoracic radiotherapy in the Saitama Medical University International Medical Center. Twenty-two patients received durvalumab consolidation therapy after CRT. Peripheral blood samples were collected before and sequentially after radiotherapy. Peripheral blood mononuclear cells were analyzed using LSR FortessaTM and CyTOFTM. ResultsAfter radiotherapy, significant increases in the percentages of CD62Llow CD4+ T cells and human leukocyte antigen-DR+ myeloid dendritic cells were observed. Mass cytometry analysis revealed that the increased CD62Llow CD4+ T cells consisted of T-bet+ CXCR3+ CD27- type 1 T helper (Th1) cells. Programmed death-1, lymphocyte-activation gene-3, and inducible T-cell costimulator expression in CD62Llow CD4+ T cells also significantly increased. Interestingly, CD62Llow CD4+ T cells initiated decreasing 4 weeks after radiotherapy in half of the patients. ConclusionsRadiotherapy induced myeloid dendritic cell activation and subsequent increase in T-bet+ CXCR3+ CD27- CD62Llow CD4+ Th1 cells. The correlation between CD4+ T-cell responses and clinical responses of durvalumab is under examination. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureO. Yamaguchi: Research grant / Funding (institution): Nihon Medi-Physics Co., Ltd.; Speaker Bureau / Expert testimony: Ono Pharmaceutical; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca. A. Mouri: Speaker Bureau / Expert testimony: Ono Pharmaceutical; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Boehringer Ingelheim. K. Kobayashi: Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony: Taiho Pharmaceutical Company; Speaker Bureau / Expert testimony: Ono Pharmaceutical Company. K. Kaira: Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony: Ono Pharmaceutical Company; Speaker Bureau / Expert testimony: Eli Lilly. H. Kagamu: Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical. All other authors have declared no conflicts of interest.

Abstract CT166: A Phase I/II, open-label, two part study of GSK3359609 in combination with tremelimumab in participants with selected, advanced solid tumors

Abstract Background: GSK3359609 (GSK609) is an inducible T cell co-stimulator (ICOS) agonist antibody and tremelimumab (treme) is a cytotoxic T-lymphocyte-antigen 4 (CTLA-4) antagonist antibody. Nonclinical and clinical studies have shown that ICOS expression on T cells is upregulated after anti-CTLA-4 treatment (tx). ICOS+ T cells have a positive association with overall survival (OS) in treme treated chemotherapy-resistant malignant mesothelioma and melanoma patients (pts). Therefore, the combination of these 2 drugs may provide greater antitumoral response than either drug alone (Coutzac C: AACR 2019 meeting abstract). Methods: This is a Phase I/II, open-label, 2-part study. In Part 1, N=~24 pts will be enrolled. The study is designed to assess treme starting at 75 mg followed by GSK609 starting at 8 mg. At dose level (DL) 1, one pt who will receive the lowest doses of both drugs will be enrolled. If no dose limiting toxicity (DLT) is observed in the DLT observation period of 28 days, then 1-3 pts will be enrolled in DL2 - DL6 in a zone-based fashion (zones include the DLs with the next highest dose of one of the two drugs - 2DL are included in each zone in this study) with different dose combinations of the drugs being evaluated. The dose of 1 of the 2 drugs will be escalated with each new DL up to the highest dose of each. If ≥ grade 2 tx-related AEs occur at DL1 or 2, additional pts will be enrolled to collect more safety information. If DLTs are observed, the bivariate Continual Reassessment Method (CRM) model will be used to guide dose recommendations. The primary objective of Part 1 will be to assess safety. Additional pts may be enrolled in Part 1 to further evaluate pharmacokinetics/pharmacodynamics (PK/PD). Part 2 is a randomized expansion enrolling recurrent/metastatic head and neck squamous cell carcinoma pts who have disease progression after platinum chemotherapy and anti-programmed death receptor protein-1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) therapy, in combination or separately. Pts may not have had ≥4 lines of prior tx in either Part 1 or 2. In Part 2, pts will be randomized 2:1 to the doses of GSK609 and treme (n=60) selected from Part 1 or to the Investigator’s choice of SOC single-agent therapy (paclitaxel, docetaxel or cetuximab) (n=30). The primary objective in Part 2 is to evaluate overall survival and the primary analysis is to perform Bayesian predictive probability of success for a future hypothetical Phase III study based on survival data. Secondary endpoints include safety, ORR, PFS, DOR, and PK while pharmacodynamic and other biomarker analyses constitute exploratory endpoints. Pts will be treated for up to 2 years with survival follow-up for up to 2 years post-tx. This study has enrolled 1 pt. Study NCT03693612 funded by GSK. Citation Format: Aaron Hansen, Raghad Abdul-Karim, Naiyer Rizvi, Danny Rischen, John Hilton, Zujun Li, Patrick Ott, Natalie Karpinich-Fedoriw, Sapna Yadavilli, Xiaowei Wang, Laurel Adams, Melody Wyres, Charles Ferte, Marc Ballas, Axel Hoos, Daniel Zandberg. A Phase I/II, open-label, two part study of GSK3359609 in combination with tremelimumab in participants with selected, advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT166.

The Infiltration of ICOS+ Cells in Nasopharyngeal Carcinoma is Beneficial for Improved Prognosis.

Nasopharyngeal carcinoma (NPC) is a highly malignant tumor, associated with poor patient prognoses, and high rates of morbidity and mortality. Currently, immune checkpoint therapy has brought new treatment strategy for NPC. The inducible T cell co-stimulator (ICOS) belongs to the B7-CD28 immunoglobulin superfamily, which is currently the subject of intense study due to great successes gained in treatment of different malignancies by disrupting their family members. However, the role of ICOS played in NPC remains poorly understood. Immunohistochemistry (IHC) was stained with the ICOS specific antibody and ICOS expression is decreased in patients with either lymphatic or distant metastasis and inversely associated with TNM stage of NPC patients. Importantly, high ICOS expression is significantly correlated with overall survival (OS) of NPC patients (N = 185, p < 0.001), and ICOS expression is also proved to be an independent prognostic factor by multivariate analysis. Surgical excised fresh NPC specimens (N = 185) were homogenized to analyze the specific cytokine expression by ELISA assay. ICOS expression level is associated with increased cytotoxic T lymphocyte number and high interferon IFNγ expression, the characteristics of Th1 cells. In addition, the correlation between the percentage of ICOS+ T cells in tumor tissue and survival was detected. Conclusively, expression of ICOS is associated with improved survival in NPC and percentage of ICOS+ cells acting as Th1 cells in primary tumor tissue may be a clinical biomarker for good prognosis of NPC patients.