scholarly journals A Cancer-Specific Qualitative Method for Estimating the Proportion of Tumor-Infiltrating Immune Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Huiting Xiao ◽  
Jiashuai Zhang ◽  
Kai Wang ◽  
Kai Song ◽  
Hailong Zheng ◽  
...  
Keyword(s):  
Immune Cells ◽  
Qualitative Method ◽  
Immune Cell ◽  
Tumor Development ◽  
Rna Seq ◽  
Batch Effects ◽  
Relative Expression Orderings ◽  
Immune Contexture ◽  
Cancer Types ◽  
Novel Method

Tumor-infiltrating immune cells are important components in the tumor microenvironment (TME) and different types of these cells exert different effects on tumor development and progression; these effects depend upon the type of cancer involved. Several methods have been developed for estimating the proportion of immune cells using bulk transcriptome data. However, there is a distinct lack of methods that are capable of predicting the immune contexture in specific types of cancer. Furthermore, the existing methods are based on absolute gene expression and are susceptible to experimental batch effects, thus resulting in incomparability across different datasets. In this study, we considered two common neoplasms as examples (colorectal cancer [CRC] and melanoma) and introduced the Tumor-infiltrating Immune Cell Proportion Estimator (TICPE), a cancer-specific qualitative method for estimating the proportion of tumor-infiltrating immune cells. The TICPE was based on the relative expression orderings (REOs) of gene pairs within a sample and is notably insensitive to batch effects. Performance evaluation using public expression data with mRNA mixtures, single-cell RNA-Seq (scRNA-Seq) data, immunohistochemistry data, and simulated bulk RNA-seq samples, indicated that the TICPE can estimate the proportion of immune cells with levels of accuracy that are clearly superior to other methods. Furthermore, we showed that the TICPE could effectively detect prognostic signals in patients with tumors and changes in the fractions of immune cells during immunotherapy in melanoma. In conclusion, our work presented a unique novel method, TICPE, to estimate the proportion of immune cells in specific cancer types and explore the effect of the infiltration of immune cells on the efficacy of immunotherapy and the prognosis of cancer. The source code for TICPE is available at https://github.com/huitingxiao/TICPE.

scholarly journals CancerImmunityQTL: a database to systematically evaluate the impact of genetic variants on immune infiltration in human cancer

2020 ◽  
Vol 49 (D1) ◽  
pp. D1065-D1073
Author(s):  
Jianbo Tian ◽  
Yimin Cai ◽  
Yue Li ◽  
Zequn Lu ◽  
Jinyu Huang ◽  
...  
Keyword(s):  
Immune Cells ◽  
Genetic Variants ◽  
Immune Cell ◽  
Human Cancer ◽  
Tumor Development ◽  
Multiple Cancer ◽  
Immune Infiltration ◽  
Cancer Types ◽  
Cell Fractions ◽  
The Impact

Abstract Tumor-infiltrating immune cells as integral component of the tumor microenvironment are associated with tumor progress, prognosis and responses to immunotherapy. Genetic variants have been demonstrated to impact tumor-infiltrating, underscoring the heritable character of immune landscape. Therefore, identification of immunity quantitative trait loci (immunQTLs), which evaluate the effect of genetic variants on immune cells infiltration, might present a critical step toward fully understanding the contribution of genetic variants in tumor development. Although emerging studies have demonstrated the determinants of germline variants on immune infiltration, no database has yet been developed to systematically analyze immunQTLs across multiple cancer types. Using genotype data from TCGA database and immune cell fractions estimated by CIBERSORT, we developed a computational pipeline to identify immunQTLs in 33 cancer types. A total of 913 immunQTLs across different cancer types were identified. Among them, 5 immunQTLs are associated with patient overall survival. Furthermore, by integrating immunQTLs with GWAS data, we identified 527 immunQTLs overlapping with known GWAS linkage disequilibrium regions. Finally, we constructed a user-friendly database, CancerImmunityQTL (http://www.cancerimmunityqtl-hust.com/) for users to browse, search and download data of interest. This database provides an informative resource to understand the germline determinants of immune infiltration in human cancer and benefit from personalized cancer immunotherapy.

scholarly journals Tumor-derived exosomes promote carcinogenesis of murine oral squamous cell carcinoma

2019 ◽  
Vol 41 (5) ◽  
pp. 625-633 ◽  
Author(s):  
Beatrice M Razzo ◽  
Nils Ludwig ◽  
Chang-Sook Hong ◽  
Priyanka Sharma ◽  
Kellsye P Fabian ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Malignant Tumors ◽  
Tumor Development ◽  
Tumor Burden ◽  
Cellular Reprogramming ◽  
Cd8 T Lymphocytes ◽  
Immune Cell Migration ◽  
Phosphate Buffered Saline ◽  
Hnscc Cell

Abstract Circulating tumor-derived exosomes (TEX) interact with a variety of cells in cancer-bearing hosts, leading to cellular reprogramming which promotes disease progression. To study TEX effects on the development of solid tumors, immunosuppressive exosomes carrying PD-L1 and FasL were isolated from supernatants of murine or human HNSCC cell lines. TEX were delivered (IV) to immunocompetent C57BL/6 mice bearing premalignant oral/esophageal lesions induced by the carcinogen, 4-nitroquinoline 1-oxide (4NQO). Progression of the premalignant oropharyngeal lesions to malignant tumors was monitored. A single TEX injection increased the number of developing tumors (6.2 versus 3.2 in control mice injected with phosphate-buffered saline; P < 0.0002) and overall tumor burden per mouse (P < 0.037). The numbers of CD4+ and CD8+ T lymphocytes infiltrating the developing tumors were coordinately reduced (P < 0.01) in mice injected with SCCVII-derived TEX relative to controls. Notably, TEX isolated from mouse or human tumors had similar effects on tumor development and immune cells. A single IV injection of TEX was sufficient to condition mice harboring premalignant OSCC lesions for accelerated tumor progression in concert with reduced immune cell migration to the tumor.

scholarly journals The Immune Endocannabinoid System of the Tumor Microenvironment

2020 ◽  
Vol 21 (23) ◽  
pp. 8929
Author(s):  
Melanie Kienzl ◽  
Julia Kargl ◽  
Rudolf Schicho
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Immune Cells ◽  
Cannabinoid Receptors ◽  
Immune Cell ◽  
Tumor Development ◽  
Endocannabinoid System ◽  
Cell Functions ◽  
In Vitro Effects

Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME. Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive. This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy.

Safety profile of INT230-6, a novel intratumoral (IT) formulation, during injections into a variety of refractory deep and superficial tumors with evidence of tumor regression and immune activation.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2602-2602
Author(s):  
Anthony B. El-Khoueiry ◽  
Jacob Stephen Thomas ◽  
Diana L. Hanna ◽  
Lillian L. Siu ◽  
Nilofer Saba Azad ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Tumor Regression ◽  
Systemic Exposure ◽  
Systemic Absorption ◽  
Frequent Adverse Event ◽  
Load Increase ◽  
Cancer Types ◽  
And Diffusion ◽  
Clinical Trial Information

2602 Background: INT230-6 is comprised of cisplatin (CIS), vinblastine (VIN) and an amphiphilic penetration enhancer which facilitates dispersion throughout tumors and diffusion into cancer cells. In preclinical experiments, INT230-6 led to necrosis and recruitment of immune cells with high rates of complete responses of injected and bystander tumors. This abstract highlights the safety and early pharmacodynamic activity of this approach. Methods: Patients with solid tumors that progressed on all standard treatments were enrolled. Dose escalation occurred by increasing number of tumors injected, loading per tumor, and total dose. INT230-6 was injected once every 2 weeks in multiple lesions for 5 sessions. Patients were monitored for safety and tolerability weekly. Pharmacokinetic(Pk) samples and peripheral blood were collected for flow cytometry and circulating cytokines. Pre and on study biopsies are ongoing. Results: 28 patients (14 unique cancer types) receiving a median of 3 prior treatments were enrolled. Doses from 0.3 ml up to-80 ml of INT230-6 were given into single lesions with some patients receiving a total of 120 mL ( = 9.7mg VIN exceeding the IV VIN dose) without significant systemic absorption or typical cytotoxic adverse events. Pk analysis suggests that systemic exposure of VIN or CIS is ~10% of injected. No DLT’s or drug-related SAE’s reported. The most frequent adverse event was grade 1 or 2 pain at injected site. Superficial tumors showed signs of response including flattening, areas of necrosis and ulceration. Tumor reduction, apparent in in both injected and bystander tumors, may indicate an abscopal effect. An increase > 30% in CD8 T-cells was seen in the blood of 3/9 evaluable patients. Conclusions: INT230-6 was safe and well tolerated in > 100 injections (28 patients) with encouraging activity and pharmacodynamic effects in advanced refractory tumors. Additional analysis of immune cells from on study biopsies will be presented. A new cohort will evaluate combination with an anti-PD1 antibody to understand if local tumor destruction can increase systemic antigen load, increase immune cell recognition and initiate a systemic immune response. Clinical trial information: NCT 03058289.

scholarly journals Paving the Way for Immunotherapy in Pediatric Acute Myeloid Leukemia: Current Knowledge and the Way Forward

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4364
Author(s):  
Joost B. Koedijk ◽  
Inge van der Werf ◽  
Friso G. Calkoen ◽  
Stefan Nierkens ◽  
Gertjan J. L. Kaspers ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Patient Care ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Current Treatment ◽  
Treatment Regimens ◽  
Cancer Types ◽  
Pediatric Aml ◽  
The Way

Immunotherapeutic agents may be an attractive option to further improve outcomes and to reduce treatment-related toxicity for pediatric AML. While improvements in outcome have been observed with immunotherapy in many cancer types, immunotherapy development and implementation into patient care for both adult and pediatric AML has been hampered by an incomplete understanding of the bone marrow environment and a paucity of tumor-specific antigens. Since only a minority of patients respond in most immunotherapy trials across different cancer types, it will be crucial to understand which children with AML are likely to respond to or may benefit from immunotherapies. Immune cell profiling efforts hold promise to answer this question, as illustrated by the development of predictive scores in solid cancers. Such information on the number and phenotype of immune cells during current treatment regimens will be pivotal to generate hypotheses on how and when to intervene with immunotherapy in pediatric AML. In this review, we discuss the current understanding of the number and phenotype of immune cells in the bone marrow in pediatric AML, ongoing immunotherapy trials and how comprehensive immune profiling efforts may pave the way for successful clinical trials (and, ultimately, implementation into patient care).

scholarly journals HGG-26. SINGLE-CELL RNA-SEQ OF PEDIATRIC HIGH-GRADE GLIOMAS IDENTIFIES COMMON ONCOGENIC PROCESSES AMONG DISTINCT TUMOR HISTOLOGIES

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i22-i22
Author(s):  
John DeSisto ◽  
Andrew Donson ◽  
Rui Fu ◽  
Bridget Sanford ◽  
Kent Riemondy ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Modalities ◽  
Patient Specific ◽  
Cell Populations ◽  
High Grade ◽  
Methylation Data ◽  
Rna Seq

Abstract Background Pediatric high-grade glioma (PHGG) is a deadly childhood brain tumor that responds poorly to treatment. PHGG comprises two major subtypes: cortical tumors with wild-type H3K27 and diffuse midline gliomas (DMG) that occur in the midline and have characteristic H3K27M mutations. Cortical PHGG is heterogeneous with multiple molecular subtypes. In order to identify underlying commonalities in cortical PHGG that might lead to better treatment modalities, we performed molecular profiling, including single-cell RNA-Seq (scRNA-Seq), on PHGG samples from Children’s Hospital Colorado. Methods Nineteen cortical PHGG tumor samples, one DMG and one normal margin sample obtained at biopsy were disaggregated to isolate viable cells. Fifteen were glioblastomas (GBM), including five with epithelioid and/or giant cell features and five radiation-induced glioblastomas (RIG). There were also four non-GBM PHGG. We performed scRNA-Seq using 10X Genomics v.3 library preparation to enable capture of infiltrating immune cells. We also performed bulk RNA-Seq and DNA methylation profiling. Results After eliminating patient-specific and cell-cycle effects, RIG, epithelioid GBM, and other GBM each formed identifiable subgroups in bulk RNA-Seq and scRNA-Seq datasets. In the scRNA-Seq data, clusters with cells from multiple tumor samples included a PDGFRA-positive population expressing oligodendrocyte progenitor markers, astrocytic, mesenchymal and stemlike populations, macrophage/monocyte immune cells, and a smaller T-cell population. Analyses of DNA methylation data showed PDGFRA and CDK4 amplification and CDKN2A deletion are common alterations among PHGG. Inferred copy number variation analysis of the single-cell data confirmed that individual tumors include populations that both include and lack the molecular alterations identified in the methylation data. RNA velocity studies to define tumor cells of origin and further analyses of the immune cell populations are underway. Conclusions Single-cell analysis of PHGG confirms a large degree of tumor heterogeneity but also shows that PHGG have stemlike, mesenchymal and immune cell populations with common characteristics.

IMMU-43. IMMUNE CONTEXTURE OF ISOCITRATE DEHYDROGENASE STRATIFIED HUMAN GLIOMAS REVEALED BY SINGLE-CELL TRANSCRIPTOMICS AND ACCESSIBLE CHROMATIN

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi102-vi102
Author(s):  
Pravesh Gupta ◽  
Minghao Dang ◽  
Dapeng Hao Hao ◽  
Krishna Bojja ◽  
Tuan M Tran ◽  
...  
Keyword(s):  
T Cells ◽  
Antigen Presentation ◽  
Single Cell ◽  
Immune Cells ◽  
Isocitrate Dehydrogenase ◽  
Zinc Finger Protein ◽  
Immune Cell ◽  
Human Gliomas ◽  
Immune Contexture ◽  
Accessible Chromatin

Abstract The immune cell composition of isocitrate dehydrogenase wild type (IDH-wt) glioma patients significantly differs compared to IDH-mutant (IDH-mut) yet a detailed and unbiased understanding of their transcriptomic and epigenetic landscapes remains elusive. To this end, we performed single-cell RNA-sequencing (scRNA-seq) and single-cell Assay for Transposase-Accessible Chromatin using sequencing (sc-ATAC-seq) on ~100,000 tumor-associated immune cells from seventeen IDH mutation classified primary and recurrent human gliomas and non-glioma brains (NGBs). Our analyses revealed sixty-two transcriptionally distinct myeloid and lymphoid cell states within and across glioma subtypes and we noted microglial attrition with increasing disease severity concomitant with invading monocyte-derived cells (MDCs) and lymphocytes. Specifically, certain microglial and monocyte-derived subpopulations were associated with antigen presentation gene modules, akin to cross-presenting dendritic cells. As tissue macrophages exhibit multifaceted polarization in response to microenvironmental cues, we clarify the existence of microglia/macrophage functional states beyond M1/M2 paradigms exemplified by the presence of palmitic-, oleic- acid, and glucocorticoid responsive polarized states. We identified cytotoxic T cells with poly-functional cytolytic states mostly in recurrent IDH-wt gliomas. Furthermore, ligand-receptor interactome analyses showed a preponderance of antigen presentation/phagocytosis over the checkpoint axis in IDH-wt compared to IDH-mut gliomas. Additionally, our sc-ATAC-seq analyses revealed differences in regulatory networks in NGBs, IDH-mut, and IDH-wt glioma-associated immune cells. In particular, we noted reduced microglial usage of an iron recycling SPIC transcription factor and Interferon Regulatory Factors (IRFs); IRF1 and IRF2 in IDH-wt relative to IDH-mut and NGBs. Unique features such as amplification of 11-Zinc Finger Protein accessibility were restricted to MDCs. Finally, sc-ATAC-seq profiles of CD8+ exhausted T cells from IDH-wt showed strong enhancer accessibility on CTLA-4, Layilin, and TIM-3 but no enrichment on PD1 was seen. In summary, our study provides unprecedented granular detail of transcriptionally and epigenomically defined glioma-specific immune contexture that can be exploited for immunotherapy applications.

scholarly journals IMMU-27. ANALYSIS OF IMMUNE SIGNATURES IN PEDIATRIC GLIOBLASTOMAS FOR PATIENT STRATIFICATION TO IMMUNOTHERAPY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii365-iii365
Author(s):  
Vidyalakshmi Chandramohan ◽  
Tyler Evangelous ◽  
Eric S Lipp ◽  
Bhavna Hora ◽  
Darell D Bigner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Cells ◽  
Immune Cells ◽  
Median Overall Survival ◽  
Immune Cell ◽  
Cell Mass ◽  
Cell Phenotype ◽  
Patient Stratification ◽  
Rna Seq ◽  
Selection Of

Abstract BACKGROUND Pediatric glioblastoma (pGBM), despite being relatively rare (incidence rate: 0.5/100,000), are a leading cause of cancer deaths in children with a median overall survival of 9–15 months. In recent years, immunotherapy has emerged as one of the more promising advances in oncology, with impressive response rates reported in several malignancies. Effective application of immunotherapy in brain tumors depends upon a better understanding of the immune cell phenotype and mechanisms of immunosuppression in these tumors. This understanding will allow for the selection of patient population who are most likely to benefit from immunotherapeutic approaches. MATERIAL AND METHODS In order to determine the frequency, distribution, and phenotype of tumor-infiltrating immune cells in pGBMs, we undertook an immunohistochemical survey on 19 recurrent pGBMs for CD3, CD8, CD4, CD163, PD-1, PD-L1, and FoxP3; RNA-Seq was also performed on a subset of 9 cases. Distribution of lymphocytes (LYMPHS) was recorded as intratumoral (IT) or perivascular (PV). RESULTS The analysis indicates intratumoral CD3+ LYMPHS are commonly <5% of tumor cell mass; however, approximately half (10/19) of these recurrent pGBM have infiltrates that range from 5 to 30% CD3+ LYMPHS. Of these, 4/10 CD3+ tumors exhibit brisk CD8+ infiltrates that are associated with PD-L1+ tumor cells. These tumors with brisk CD3+/CD8+ LYMPHS and PD-L1+ tumor cells were associated with longer survivals. The data were confirmed by RNA-seq analysis. CONCLUSION PD-L1+ pGBMs associated with CD3+/CD8+ LYMPH infiltrates deserve further investigation as candidates for immunotherapy.

scholarly journals Exercise-Induced Changes in Tumor Growth via Tumor Immunity

Sports ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 46
Author(s):  
Polyxeni Spiliopoulou ◽  
Maria Gavriatopoulou ◽  
Efstathios Kastritis ◽  
Meletios Athanasios Dimopoulos ◽  
Gerasimos Terzis
Keyword(s):  
Immune System ◽  
Physical Exercise ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
Immune Cells ◽  
Immune Cell ◽  
Tumor Development ◽  
Exercise Induced ◽  
Induced Changes

Immunity in the tumor microenvironment plays a central role in tumor development. Cytotoxic immune cells act against tumors, while tumors manage to trigger immunosuppressive mechanisms for defense. One bout of physical exercise acutely regulates the immune system inducing short-term redistribution of immune cells among body organs. Repeated acute immune cell mobilization with continuing exercise training results in long-term adaptations. These long-term exercise-induced changes in the immune system arise both in healthy and in diseased populations, including cancer patients. Recent preclinical studies indicate that physical exercise may have a positive impact on intra-tumoral immune cell processes, resulting in tumor suppression. This short narrative review describes the effect of physical exercise on tumor growth as detected via changes in tumor immunity. Research evidence shows that exercise may improve tumor-suppressive functions and may reduce tumor-progressive responses and mechanisms of immune cells, controlling tumor development. Specifically, it seems that exercise in rodents triggers shifts in tumor infiltration of macrophages, neutrophils, natural killer cells, cytotoxic and regulatory T lymphocytes, resulting in tumor suppression. These recent promising data suggest that physical exercise could be combined with anticancer immunotherapies, although exercise parameters like intensity, duration, and frequency need to be evaluated in more detail. More research is needed to investigate the effect of exercise in other immune cell subtypes and their possible connection with tumor growth, whilst information from human tumors is also required.

scholarly journals Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword

2020 ◽  
Vol 21 (12) ◽  
pp. 4346 ◽  
Author(s):  
Anthony M. Battram ◽  
Mireia Bachiller ◽  
Beatriz Martín-Antonio
Keyword(s):  
Tumor Cells ◽  
Cancer Progression ◽  
Immune Cells ◽  
Immune Cell ◽  
Tumor Development ◽  
Cell Senescence ◽  
Therapeutic Interventions ◽  
Main Role ◽  
Suppressor Mechanism

Cellular senescence was first described as a physiological tumor cell suppressor mechanism that leads to cell growth arrest with production of the senescence-associated secretory phenotype known as SASP. The main role of SASP in physiological conditions is to attract immune cells to clear senescent cells avoiding tumor development. However, senescence can be damage-associated and, depending on the nature of these stimuli, additional types of senescence have been described. In the context of cancer, damage-associated senescence has been described as a consequence of chemotherapy treatments that were initially thought of as a tumor suppressor mechanism. However, in certain contexts, senescence after chemotherapy can promote cancer progression, especially when immune cells become senescent and cannot clear senescent tumor cells. Moreover, aging itself leads to continuous inflammaging and immunosenescence which are responsible for rewiring immune cells to become defective in their functionality. Here, we define different types of senescence, pathways that activate them, and functions of SASP in these events. Additionally, we describe the role of senescence in cancer and its treatments, including how aging and chemotherapy contribute to senescence in tumor cells, before focusing on immune cell senescence and its role in cancer. Finally, we discuss potential therapeutic interventions to reverse cell senescence.

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