Overexpression of LILRB2 (ILT4) is correlated with immunosuppressive immune infiltration in lung adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20519-e20519
Author(s):  
Butuo Li ◽  
Chao Jiang ◽  
Shijiang Wang ◽  
Xuanzong Li ◽  
Yiyue Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Adenocarcinoma ◽  
Objective Response ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
M2 Macrophage ◽  
Immune Infiltration ◽  
T Cell Infiltration ◽  
The Relationship

e20519 Background: Immune checkpoint inhibitors have revolutionized the patterns of tumor treatment with significantly improved survival. However, it’s worth noting that the objective response rate of PD-1/PD-L1 inhibitors monotherapy is just 20% in non-small cell lung cancer (NSCLC) patients, and biomarkers for the prognosis of patients receiving PD-1/PD-L1 inhibitors are urgently needed. LILRB2 (ILT4) is known as an immunosuppressive molecule and promotes the development and progression of NSCLC. However, the relationship between LILRB2 expression and immune microenvironment remains unclear in patients with lung adenocarcinoma. Methods: Expression profile and corresponding clinicopathological data of patients with lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) database. TIMER 2.0 was used to investigate the relationship between LILRB2 expression and immune infiltrates, including T cell subset, macrophage and so on. Cox proportional hazard model was also performed to evaluate the role LILRB2 expression and immune infiltrations in prognostic prediction of patients with lung adenocarcinoma. Results: 515 patients with lung adenocarcinoma were included in analysis from TCGA dataset. LILRB2 expression was found to have significant negative correlation with CD8+ T cell infiltration (P = 0.0012), and positive correlation with CD4+ T cell infiltration (P < 0.001). There were also significant positive correlations between LILRB2 expression and Treg (P = 0.0083), cancer associated fibroblast (P < 0.001), monocyte (P < 0.001), M2 macrophage (P < 0.001) infiltration, which was regarded as the marker of immunosuppressive microenvironment. Notably, there were also significant association between the expression of LILRB2 and PD-1 (P < 0.001) and PD-L1(P < 0.001). In terms of survival analysis, high level of Treg (HR = 0.86, P = 0.03) and M2 macrophage (HR = 0.84, P = 0.017) infiltration was associated with poor prognosis of patients with lung adenocarcinoma. However, the level of CD8+T cell (HR = 0.93, P = 0.298), CD4+ T cell (HR = 0.933, P = 0.321), and LILRB2 expression (P = 0.56) was not associated with the survival of patient with lung adenocarcinoma. Conclusions: The overexpression of LILRB2 is significantly correlated with immunosuppressive immune infiltration and microenvironment in lung adenocarcinoma and might be the potential predictive biomarkers for the PD-1/PD-L1 inhibitors.

scholarly journals Higher cytolytic score correlates with an immunosuppressive tumor microenvironment and reduced survival in glioblastoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alexander F. Haddad ◽  
Jia-Shu Chen ◽  
Taemin Oh ◽  
Matheus P. Pereira ◽  
Rushikesh S. Joshi ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Cell Types ◽  
Cd8 T Cell ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Sequencing Data ◽  
Gene Score ◽  
T Cell Infiltration ◽  
The Relationship

Abstract Cytolytic score (CYT), calculated from mRNA expression levels of granzyme and perforin, positively correlates with CD8+ T cell infiltration/activity in a variety of cancers. Unlike other cancers, higher CYT has been associated with worse prognosis in glioblastoma (GBM). To address this discrepancy, we sought to investigate the relationship between CYT and immune checkpoint gene score (ICGscore), as well as their correlation with patient survival and tumor immune cell infiltration. Clinical and RNA-sequencing data for patients with newly diagnosed GBM were obtained from The Cancer Genome Atlas. Maximally-selected rank statistics was used to dichotomize subgroups. CIBERSORT was used to estimate abudence of immune cell-types. Spearman correlation was used to characterize the relationship between CYT and ICGscore. Kaplan–Meier curves were generated for survival analysis. Overall, 28/151 patients had high CYT. High CYT was associated with a mesenchymal subtype (p < 0.001) and worse survival (7.45 vs. 12.2 months, p < 0.001). There were no differences in patient demographics, IDH/MGMT mutation status, or treatment. On subgroup analysis, patients with high CYT/ICGscore had significantly increased CD8+ infiltration (p < 0.001), as expected, and worse survival (HR 0.445, p < 0.01). Furthermore, CYT strongly correlated with ICGscore (RS = 0.675, p < 0.001). The high CYT/ICGscore subgroup was associated with greater infiltration of M2 macrophages (p = 0.011) and neutrophils (p = 0.055). Our study highlights a multidimensional immunosuppressive GBM microenvironment in patients with higher CYT and potentially identifies patients with high CYT/ICGscore as a subgroup that may particularly benefit from multi-faceted immunotherapies, given their already elevated tumor CD8+ T cell levels.

scholarly journals m6A Modification Patterns Identify a Subset of Follicular Lymphoma Harboring an Exhausted Tumor Microenvironment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4486-4486
Author(s):  
Xianhuo Wang ◽  
Tingting Zhang ◽  
Hengqi Liu ◽  
Sicong Zhang ◽  
Kai Fu ◽  
...  
Keyword(s):  
T Cell ◽  
Follicular Lymphoma ◽  
Cd8 T Cell ◽  
Gene Signature ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Biological Processes ◽  
T Cell Infiltration ◽  
Cluster A

Abstract Background: Epigenetic dysregulation is important for the pathogenesis of follicular lymphoma (FL). N6-methyladenosine (m6A) is the most common post-transcriptional modification of mRNA. The m6A modification affects a wide range of cellular processes, including RNA stability, export, splicing or translation, and is extensively involved in the development and progression of multiple non-hematological and hematological malignancies. However, the role of m6A modification in FL remain largely unknown. Methods: We comprehensively evaluated the m6A modification patterns of 351 FL patients from three cohorts based on 16 m6A regulators and constructed the m6A gene signature the by unsupervised clustering analysis. The m6A score was then established using principal component analysis. The association between m6A modification patterns and prognostic implications, biological processes, and microenvironment characterizations in FL were further investigated. Results: A total of 16 m6A regulators were finally identified in this study, including 8 writers, 7 readers and one eraser. Two distinct m6A modification patterns, termed as m6A cluster A and m6A cluster B respectively, were identified based on the similarity displayed by the expression levels of 16 m6A regulators and the proportion of ambiguous clustering measure. Patients with m6A cluster A had significantly poorer survival than those with m6A cluster B (p=0.0085) and showed enrichment in cell cycle, DNA replication and mismatch repair biological processes. However, patients with m6A cluster B were markedly enriched in MAPK pathway, WNT pathway, mTOR pathway, natural killer cell mediated cototoxicity, cytokine-cytokine receptor interaction and T-cell receptor pathway. Additionally, myeloid dendritic cell and CD8 + T cell were significantly enriched in m6A cluster A, nevertheless CD4 + T cell was abundant in m6A cluster B. Base on the DEGs between m6A cluster A and m6A cluster B, a m6A gene signature was further constructed, namely m6A gene signature A and m6A gene signature B. Patients with m6A gene signature B experienced worse outcome than those with m6A gene signature A. Simultaneously, a m6A scoring model was also established to quantify the m6A modification pattern of individual patients with FL. Patients with low m6A score presented a prominent inferior survival than those with high m6A score (p&lt; 0.0001). The median survival times for patients with low and high m6A score were 8.84 (95% confidence interval [CI]: 7.251-10.429) and 15.73 years (95% CI: 11.729-19.731), respectively. High m6A score group was remarkably riched in macrophage cell and CD4 + T cell infiltration, while low m6A score group exhibited significantly increased myeloid dendritic cell and CD8 + T cell infiltration, suggesting that m6A score could distinguish populations with distinct immune cell infiltration characteristics. GSVA analysis showed that the expression of genes involved in the immune and inflammatory response was significantly upregulated in low m6A score group. But we finally found that the CD8 + T cells in low m6A score group kept in a state of exhaustion, leading to that exhausted T cells were enriched in low m6A score group. The expression of PD-1 and PD-L1 in low m6A score group was also higher than those in high m6A score group. GSEA analysis showed that low m6A score group exhibited an enhanced IFN-γ response. Finally, we verified the value of the m6A score for predicting response to anti-PD-L1 antibody in external immunotherapy cohort (IMvigor210), and found that patients with low m6A score exhibited significantly clinical benefits and a markedly prolonged survival from anti-PD-L1 therapy. Conclusions: This is the first time to comprehensively investigate the role of m6A modification in FL. The m6A score identifies a subset of follicular lymphoma harboring an exhausted tumor microenvironment and helps for the selection of patients for immunotherapy, guiding the personalized immunotherapy in FL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract 4303: Heme Oxygenase 1 Expression in Dendritic Cells Drives Cd4+ T Cell Activation in Transplantation Atherosclerosis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Annemarie M Noordeloos ◽  
C Cheng ◽  
E van Deel ◽  
D Tempel ◽  
M L Simoons ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Heme Oxygenase 1 ◽  
Cell Ratio ◽  
Mhc Ii ◽  
T Cell Infiltration ◽  
T Cell Priming

Although over-expression of heme oxygenase-1 (HO-1) attenuates transplantation arteriosclerosis, the mechanism by which HO-1 exerts its protective effect remains unclear. In order to investigate the effect of HO-1 expression specifically in the dendritic cell (DC) in the context of transplantation atherosclerosis, we studied the effect of HO1-deficient versus wildtype (WT) DCs on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. At day 0 C57bl6 mice received either WT (N=7) or HO1-knockout DCs (N=7) pre-sensitized with Balb/c splenocytes lysate. At day 10 an allogenic aorta segment derived from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice. 14 days post transplantation, the grafts were harvested and analyzed by imumnohistology. Adoptive transfer of HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 versus 38428 μm2 P<0.05). HO-1 deficient DCs also increased medial thickeness (15936 versus 12034 μm2 P<0.05), reduced intimal VSMCs content (46 versus 75% P<0.05) and resulted in more prominent medial cell infiltration (461 versus 232 μm2 P<0.05). In the transplanted aorta of the with HO-1 nullizygous DCs treated recipient group, an increase in CD4+ T-cell infiltration (9.5 versus 0.2% in WT P<0.05) and IgG deposition, concomitant to a decrease of CD8+ T cell infiltration (8.1 versus 14.3%, P<0.05) was observed. In line with these observations, in vitro analysis of HO-1 deficiency in DC function showed an increased priming potential for CD4+ T cells, thereby increasing the CD4+/CD8+ T cell ratio. Increased efficiency in CD4+ T cell priming by HO-1 deficient DCs was facilitated by a higher cell surface level of MHC II. Further studies indicated that HO-1 deficiency increased STAT1 phosphorylation, thereby enhancing CIITA gene expression that lead to increased MHC II levels on the DCs cell surface. HO-1 deficiency in dendritic cells increases vascular cell infiltration with a higher CD4+/CD8 T-cell ratio in vascular allografts resulting in an augmented form of transplantation arteriosclerosis. This effect is facilitated by a STAT1-CIITA-MHCII dependent intracellular pathway.

scholarly journals Tertiary Lymphoid Structure and CD8 T Cell Exclusion in Minimally Invasive Adenocarcinoma

2020 ◽  
Author(s):  
Jin Wang ◽  
Dongbo Jiang ◽  
Xiaoqi Zheng ◽  
Wang Li ◽  
Tian Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Minimally Invasive ◽  
Lung Adenocarcinoma ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Rna Seq ◽  
Invasive Adenocarcinoma ◽  
T Cell Infiltration ◽  
Minimally Invasive Adenocarcinoma

Lung adenocarcinoma is the leading cause of cancer death. To characterize the tumor microenvironment (TME) of early-stage lung adenocarcinoma, we performed RNA-seq profiling on 59 pairs of minimally invasive adenocarcinoma (MIA) tumors and matched adjacent normal lung tissues from Chinese patients. We observed mucin over-expression and glycosylation, and altered cytokine-cytokine interactions in MIA tumors, which also had distinct adaptive immune TME of higher CD4+ T cell infiltration, higher plasma B cell activation, and lower CD8+ T cell infiltration. The high expression of markers for B cells, activated CD4 T cells, and follicular helper T (Tfh) cells in MIA implicated the formation of tertiary lymphoid structures (TLS), which were supported by two independent single-cell RNA-seq data. Multiplex immunohistochemistry (mIHC) staining of 22 MIA tumors validated TLS formation and revealed an enrichment of follicular regulatory T cells (Tfr) in TLS follicles, which may explain the lower CD8+ T cell infiltration and attenuated anti-tumor immunity in MIA.

CD8 + T Cell Infiltration Predicts Chemoradiosensitivity in Nasopharyngeal or Oropharyngeal Cancer

2020 ◽  
Vol 131 (4) ◽  
Author(s):  
Toshihiko Kawaguchi ◽  
Takeharu Ono ◽  
Fumihiko Sato ◽  
Akihiko Kawahara ◽  
Tatsuyuki Kakuma ◽  
...  
Keyword(s):  
T Cell ◽  
Oropharyngeal Cancer ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration

Abstract 760: Heme Oxygenase-1 expression in Dendritic Cells determines the Outcome of Transplantation Arteriosclerosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Annemarie Noordeloos ◽  
Elza van Deel ◽  
Denise Hermes ◽  
Maarten L Simoons ◽  
Dirk J Duncker ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Heme Oxygenase ◽  
T Cell Activation ◽  
Neointimal Hyperplasia ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Heme Oxygenase 1 ◽  
T Cell Infiltration ◽  
Mhcii Expression

Introduction: Although expression of heme oxygenase-1 (HO1) attenuates transplantation arteriosclerosis, the mechanism by which HO1 exerts its protective effect remains unclear. We studied the effect of HO1-deficient vs. wildtype (WT) dendritic cells (DCs) on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. Methods: At day 0 C57bl6 mice received either WT (n=6) or HO1-knockout DCs (n=6) pre-sensitized with Balb/c splenocytes lysate to accelerate the development of arteriosclerosis. At day 10 an aorta segment from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice.14 days after transplantation allografts were excised and processed for immunohistochemical analysis. Results: HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 vs. 46114μm 2 P<0.05) and incidence of intima formation (83 vs. 50% in WT DC). HO1 deficient DCs also increased medial thickeness (15936 vs.12034 μm 2 P<0.05) and intimal VSMCs content (76 vs. 46% P<0.05) and resulted in more prominent medial cell infiltration (461μm 2 vs. 232μm 2 P<0.05). Although HO1 deficient and WT DCs could be detected in allografts, HO1-nullizygous DCs induced an increase in CD4+ T-cell infiltration (9.5 vs. 0.1% in WT P<0.05) concomitant to a decrease of CD8+ T cell infiltration (8 vs.14%, P<0.05). In line with these observations Affymetrix microarray analysis confirmed that HO1 deletion in DCs was associated with a significant downregulation of MHCII-H2A expression (associated with CD4+T-cell activation) and induction of inhibitors of MHCII expression (including IK protein) whereas MHC I expression remained unchanged. Conclusions: HO1 expression in dendritic cells increases vascular cell infiltration with a higher CD8+/CD4+ T-cell ratio by stabilizing MHCII expression in vascular allografts resulting in inhibition of neointima formation and hence improved allograft survival.

scholarly journals 342 Combining enadenotucirev and nivolumab increased tumour immune cell infiltration/activation in patients with microsatellite-stable/instability-low metastatic colorectal cancer in a phase 1 study

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A368-A369
Author(s):  
David Krige ◽  
Marwan Fakih ◽  
Lee Rosen ◽  
Ding Wang ◽  
Wael Harb ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
Cd8 T Cell ◽  
Post Treatment ◽  
Institutional Review Board ◽  
Cell Infiltration ◽  
Link Type ◽  
T Cell Infiltration ◽  
Institutional Review

BackgroundMicrosatellite-stable (MSS) and instability-low (MSI-L) metastatic colorectal cancer (mCRC) are typically characterised as ”immune-excluded/desert” tumour microenvironments lacking T-cell infiltration. Anti-PD-1 monotherapy has little clinical benefit in MSS/MSI-L mCRC1 and knowledge of the effects of PD-1 inhibition on T-cell activation/infiltration in this population is limited. Novel combination therapies to overcome anti-PD-1 resistance are required. SPICE is a multicentre, open-label, phase 1 study of the tumour-selective chimeric Ad11/Ad3 group B oncolytic adenovirus enadenotucirev plus nivolumab in patients with metastatic/advanced epithelial tumours refractory to standard therapy. Preliminary data from patients with MSS/MSI-L mCRC demonstrated a median overall survival of 14 months, manageable tolerability and intratumoural T-cell infiltration.2 Here we characterise the immunological effects of tumour re-engineering with enadenotucirev in combination with nivolumab in patients with MSS/MSI-L mCRC.MethodsPatients received increasing doses and/or cycles of intravenous enadenotucirev followed by up to 8 cycles of nivolumab as previously described.2 Wherever possible, pre- and post-treatment (~5 weeks post-first enadenotucirev) biopsies were collected; samples were analysed using immunohistochemistry and automated image analysis. Peripheral blood mononuclear cell immunophenotyping (multiparameter flow cytometry) and serum cytokines were assessed at multiple times.Results43 patients with mCRC were treated (86% MSS/MSI-L; 14% unknown). Among the 13 patients (12/13 MSS/MSI-L; 1/13 unknown) with matched biopsies, 11 had increased intratumoural and stromal CD8+ T-cell infiltration in post-treatment biopsies (median [Q1-Q3] fold changes 6.5× [1.5–25.4] and 1.9× [1.5–3.9], respectively; figure 1). CD4+ T-cell density increased in 10/13 patients and 8/13 patients had increased proportions of PD-L1+ immune cells. Increases in CD8 T-cell proliferation (Ki67; 7/9 patients) and cytolytic activity (Granzyme B; 7/13 patients) markers were seen. 4/13 patients converted from a ”desert” to an ”inflamed” immune phenotype (pathologist scored CD8/pan-cytokeratin staining). Immunophenotyping showed trends towards increased T-cell activation (CD38+ and HLA-DR+ CD8+ T cell populations) post-treatment (9/10 patients), including in one patient who had only received enadenotucirev prior to sampling. Persistent increases in inflammatory cytokines (IFNγ, IL-12p70, IL-17a) were seen in two patients from ~Day 15, including one who achieved a sustained objective response.Abstract 342 Figure 1Tumour immune cell infiltration following treatment with enadenotucirev plus nivolumabConclusionsThese data show that intravenous enadenotucirev plus nivolumab can induce immune infiltration/activation within MSS/MSI-L mCRC. These encouraging findings suggest that immune activation can be achieved even in ”immune-excluded/desert” tumours. SPICE has been closed following completion of dose-escalation. Efforts are now focused on the development of next-generation variants of enadenotucirev designed to further re-programme the tumour microenvironment by expressing immune-enhancer transgenes (T-SIGn vectors); these studies are ongoing (NCT04830592, NCT04053283, NCT03852511).AcknowledgementsThis study was funded by PsiOxus Therapeutics Limited and Bristol Myers Squibb. Medical writing support: Lola Parfitt, MRes, of PsiOxus Therapeutics Limited.Trial RegistrationEudraCT number2017-001231-39NCT number: NCT02636036ReferencesKawazoe A, Kuboki Y, Shinozaki E, et al. Multicenter phase I/II trial of napabucasin and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503/SCOOP trial). Clin Cancer Res 2020;26:5887–5894.Fakih M, Wang D, Harb W, et al. SPICE: a phase I multicenter study of enadenotucirev in combination with nivolumab in tumors of epithelial origin: an analysis of the metastatic colorectal cancer patients in the dose escalation phase. Ann Oncol 2019:30(suppl_5):v252.Ethics ApprovalThe study was approved by the WCG Institutional Review Board (study approval number 20152656), UCLA Institutional Review Board (study approval number IRB#15-002010), Vanderbilt Institutional Review Board (study approval number IRB #171453) and Henry Ford Institutional Review Board (study approval number IRB #10349).

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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