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.

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 Characteristics of immune cell infiltration landscape in colorectal cancer to Aid in Immunotherapy

2021 ◽  
Author(s):  
Fei Kuang ◽  
De Luo ◽  
Mengjia Zhou ◽  
Juan Du ◽  
Yuee Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cancer Progression ◽  
Immune Cells ◽  
Immune Cell ◽  
Clinical Work ◽  
Cell Infiltration ◽  
Cancer Type ◽  
Immune Cell Infiltration ◽  
T Cell Infiltration

Abstract The tumor microenvironment (TME) is a complex environment composed of a variety of stromal cells and immune cells that infiltrate the tumor space. Recent clinical work has clearly shown such intratumoral immune cell infiltration (ICI) to be closely related to colorectal cancer (CRC) patient survival, yet the specific landscape of infiltrating immune cells associated with this cancer type remains to be clarified. We utilized two computational algorithms to evaluate the ICI status of 712 CRC patients, stratifying these patients into two ICI status-based patterns and assigning ICI scores through the use of principal component analyses. We found that the overall survival (OS) of patients with higher ICI scores was significantly longer than that of patients with low ICI scores. When ICI scores were combined with the results of tumor mutational burden (TMB) analyses, we determined that CRC patients with both high ICI scores and low TMB exhibited the best survival outcomes. High expression of MARCO in those patients with low ICI scores was correlated with reduced natural killer (NK) and effector T cell infiltration and with increased regulatory T cell infiltration, suggesting that these factors may be linked to poor patient prognosis. These results suggest ICI scores to be a valuable biomarker for the prognostic evaluation of CRC patients. Future efforts to analyze the ICI patterns of larger patient sample cohorts will help to extend these analyses, offering new insights into the role of the TME in cancer progression while highlighting novel immunotherapeutic approaches to treating this cancer type.

scholarly journals Tumor mutation burden in connection with immune-related survival in uterine corpus endometrial carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ling Zhao ◽  
Xueshu Fu ◽  
Xiling Han ◽  
Yanjun Yu ◽  
Yaping Ye ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Prognostic Models ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Tumor Mutation Burden ◽  
Immune Genes ◽  
Mutation Burden

Abstract Background UCEC is the most common gynecological malignancy in many countries, and its mechanism of occurrence and development is related to tumor mutation burden (TMB) and immune cell infiltration. Therefore, it is necessary to systematically explore the TMB-related gene profile in immune cells to improve the prognosis of UCEC. Methods We integrated TMB-related genes with basic clinical information of UCEC patients based on TCGA dataset. Differentially expressed genes (DEGs) were selected through differential expression screening, PPI, and enrichment analysis. Additionally, we analyzed the components of immune cell infiltration of the DEGs to obtain the differential immunity-related genes. A single factor and multifactor Cox regression analyses were conducted to establish new prognostic indicators of OS and DFS based on TMB-related immune genes. To further study the correlation between survival and immune cell infiltration, a Cox model based on these immune infiltration compositions was built. Using the clinical variables, we established nomograms for OS and DFS. Results 393 DEGs were significantly associated with clinical outcomes and the immune component in patients with UCEC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, Genomes (KEGG) pathway and protein-protein interaction network (PPI) analyses revealed the role of these genes and information on related pathways. Then, two prognostic models were established based on the differential immune genes for OS (GFAP and MX2) and DFS (MX2, GFAP, IGHM, FGF20, and TRAV21). In DFS, the differential immune genes were related to CD4+ T cell, CD8+ T cell, macrophage, and neutrophil (all P < 0.05). B cell and CD8+ T cell were independent prognostic factors from among the immune cell elements in UCEC. Finally, the risk scores of these models were combined with the clinical elements-based nomogram models, and the AUC values were all over 0.7. Conclusions Our results identified several clinically significant differential immune genes and established relevant prognostic models, providing a basis for the molecular analysis of TMB and immune cells in UCEC, and identified potential prognostic and immune-related genes for UCEC. We added clinical related conditions for further analysis to confirm the identity of the genes and clinical elements-based models.

scholarly journals Choroid Plexus-Selective Inactivation of Adenosine A2A Receptors Protects Against T Cell Infiltration And Experimental Autoimmune Encephalomyelitis

2021 ◽  
Author(s):  
Wu Zheng ◽  
Yijia Feng ◽  
Zhenhai Zeng ◽  
Mengqian Ye ◽  
Huiping Shang ◽  
...  
Keyword(s):  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Cell Trafficking ◽  
Autoimmune Encephalomyelitis ◽  
Post Immunization ◽  
T Cell Infiltration ◽  
Experimental Autoimmune

Abstract Background: Multiple sclerosis (MS) is one of the most common autoimmune disorders characterized by the infiltration of immune cells into the brain and demyelination. The unwanted immunosuppressive side effect of therapeutically successful natalizumab led us to focus on choroid plexus (CP), a key site for the first wave of immune cell infiltration in experimental autoimmune encephalomyelitis (EAE), for the control of immune cells trafficking. Adenosine A2A receptor (A2AR) is emerging as a potential pharmacological target to control EAE pathogenesis; however, the cellular basis for the A2AR-mediated protection remains undetermined. Methods: In EAE model, we assessed A2AR expression and leukocyte trafficking determinants in CP by immunohistochemistry and qPCR analyses. We determined the effect of the A2AR antagonist KW6002 treatment at days 8-12 or 8-14 post-immunization on T cell infiltration across CP and EAE pathology. We determined the critical role of the CP-A2AR on T cell infiltration and EAE pathology by focal knockdown the CP-A2AR with intracerebroventricular injection of CRE-TAT recombinase into the A2ARflox/flox mice. In cultured CP epithelium, we also evaluated the effect of overexpression of A2ARs or the A2AR agonist CGS21680 treatment on CP permeability and lymphocytes migration. Results: We found the specific upregulation of A2AR in CP in association with enhanced CP gateway activity peaked at day 12 post-immunization in EAE mice. Furthermore, the KW6002 treatment at days 8-12 or 8-14 post-immunization reduced T-cell trafficking across CP and attenuated EAE pathology. Importantly, focal CP-A2AR knockdown attenuated pathogenic infiltration of Th17+ cells across CP via inhibiting CCR6-CCL20 axis through NFκB / STAT3 pathway and protected against EAE pathology. Lastly, activation of A2AR in cultured epithelium by A2AR overexpression or CGS21680 treatment increased the permeability of CP epithelium and facilitated lymphocytes migration. Conclusion: These findings define the CP niche as one of the primary sites of A2AR action whereby A2AR antagonists confer protection against EAE pathology. Thus, pharmacological targeting of the CP-A2AR represents a novel therapeutic strategy for MS by controlling immune cell trafficking across CP.

Immunogenomic characterization of advanced clear cell renal cell carcinoma treated with PD-1 blockade.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5010-5010 ◽  
Author(s):  
David A. Braun ◽  
Yue Hou ◽  
Ziad Bakouny ◽  
Miriam Ficial ◽  
Miriam Sant'Angelo ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cell ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Cell Renal Cell Carcinoma ◽  
Mtor Inhibition ◽  
T Cell Infiltration

5010 Background: Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Further, the common paradigm in solid tumor immunology that pre-existing CD8+ T cell infiltration, in combination with high numbers of nonsynonymous mutations (which, in the context of diverse HLA class I alleles, may be presented as neoantigens) drives response to PD-1 blockade, has not been thoroughly explored in ccRCC. Methods: We analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials (CheckMate 009, CheckMate 010, CheckMate 025) of treatment with PD-1 blockade (n = 362) or mTOR inhibition (as control arm; n = 230) by whole-exome (n = 454) and RNA-sequencing (n = 311), integrated with CD8 immunofluorescence analysis (n = 219), to uncover the immunogenomic determinants of therapeutic response and survival. Wilcoxon rank-sum test was used to compare somatic alteration burden between clinical benefit (CB) v.s no CB (NCB); Fisher’s exact test was used to compare mutations and copy number alteration by infiltration state; and hazard ratio (HR) was calculated from Cox PH model for progression-free (PFS) and overall survival (OS) endpoints. All tests were at a significance level of p < 0.05. Results: Conventional genomic markers (tumor mutation burden, p = 0.81; neoantigen load, p = 0.47 for CB vs. NCB) and degree of CD8+ T cell infiltration (p = 0.88 for PFS; p = 0.65 for OS) were not associated with clinical response or altered survival with PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 22% having an immune desert phenotype and 5% with an immune excluded phenotype. Our analysis revealed that CD8+ T cell infiltrated tumors are depleted of clinically favorable PBRM1 mutations (p = 0.013) and enriched for unfavorable chromosomal losses of 9p21.3 (p < 0.001) when compared to non-infiltrated tumors. When found within infiltrated tumors, del(9p21.3) was associated with worse CB rate (36% (9/25) for del(9p21.3) vs. 88% (7/8) for wildtype at that locus, p = 0.017) and worse survival (HR = 2.38, p = 0.01 for PFS; HR = 2.44, p = 0.01 for OS) with PD-1 blockade. Conclusions: These data demonstrate how the potential interplay of immunophenotypes with somatic mutations and chromosomal alterations impacts therapeutic efficacy in advanced ccRCC.

scholarly journals Biomarkers Associated with CD8+ T Cell Infiltration in Childhood AML

2021 ◽  
Author(s):  
Jiafeng Zheng ◽  
Caili Zhou ◽  
Tongqiang Zhang ◽  
Wei Guo ◽  
Xiaojian Cui ◽  
...  
Keyword(s):  
T Cell ◽  
Whole Blood ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Joint Analysis ◽  
Pcr Analysis ◽  
High Morbidity ◽  
T Cell Infiltration ◽  
Childhood Aml

Abstract Acute myeloid leukemia (AML) is a common hematological malignant tumor in children. AML is characterized by high morbidity, recurrence and mortality rates worldwide. Immune cell infiltration in tumor microenvironment plays an important role in tumor progression. This study aimed at exploring biomarkers related to CD8+T cell infiltration in children with AML. Transcriptome data and clinical data were retrieved from TARGET database. We collected whole blood samples from some AML children to verify the results. Through the joint analysis of the data of multiple databases we found that CAMK2D, MPZL3, MSL3 are associated with CD8+ immune infiltration. Through PCR analysis, it was found that CAMK2D, MPZL3, MSL3 was highly expressed in the whole blood of children with AML. Analysis showed that CAMK2D, MPZL3 and MSL3 are potential clinical prognostic markers related to CD8+T cell infiltration in children with AML. The findings of this study show that CAMK2D, MPZL3, MSL3 are implicated in prognosis of AML. Notably, the three genes are implicated in CD8+T cells-related pathways.

scholarly journals Identification of biomarkers related to CD8+ T cell infiltration with gene co-expression network in clear cell renal cell carcinoma

Aging ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 3694-3712 ◽  
Author(s):  
Jiaxing Lin ◽  
Meng Yu ◽  
Xiao Xu ◽  
Yutao Wang ◽  
Haotian Xing ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cell ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Cell Renal Cell Carcinoma ◽  
T Cell Infiltration

scholarly journals Modelling the interplay between the CD4$$^{+}$$/CD8$$^{+}$$ T-cell ratio and the expression of MHC-I in tumours

2021 ◽  
Vol 83 (1) ◽  
Author(s):  
Christian John Hurry ◽  
Alexander Mozeika ◽  
Alessia Annibale
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Critical Level ◽  
Cell Infiltration ◽  
Cytotoxic T Cell ◽  
Mhc I ◽  
Cell Ratio ◽  
T Cell Infiltration ◽  
Immunological Mechanisms ◽  
Tcr Repertoire

AbstractDescribing the anti-tumour immune response as a series of cellular kinetic reactions from known immunological mechanisms, we create a mathematical model that shows the CD4$$^{+}$$ + /CD8$$^{+}$$ + T-cell ratio, T-cell infiltration and the expression of MHC-I to be interacting factors in tumour elimination. Methods from dynamical systems theory and non-equilibrium statistical mechanics are used to model the T-cell dependent anti-tumour immune response. Our model predicts a critical level of MHC-I expression which determines whether or not the tumour escapes the immune response. This critical level of MHC-I depends on the helper/cytotoxic T-cell ratio. However, our model also suggests that the immune system is robust against small changes in this ratio. We also find that T-cell infiltration and the specificity of the intra-tumour TCR repertoire will affect the critical MHC-I expression. Our work suggests that the functional form of the time evolution of MHC-I expression may explain the qualitative behaviour of tumour growth seen in patients.

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