Germline variants that influence the tumor immune microenvironment also drive response to immunotherapy

With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer risk screening and treatment strategies. Using genotypes from over 8,000 European individuals in The Cancer Genome Atlas (TCGA) and 137 heritable tumor immune phenotype components (IP components), we identified and investigated 482 TIME associations and 475 unique TIME-associated variants. Many TIME-associated variants influence gene activities in specific immune cell subsets, such as macrophages and dendritic cells, and interact to promote more extreme TIME phenotypes. TIME-associated variants were predictive of immunotherapy response in human cohorts treated with immune-checkpoint blockade (ICB) in 3 cancer types, causally implicating specific immune-related genes that modulate myeloid cells of the TIME. Moreover, we validated the function of these genes in driving tumor response to ICB in preclinical studies. Through an integrative approach, we link host genetics to TIME characteristics, informing novel biomarkers for cancer risk and target identification in immunotherapy.

Download Full-text

RNA N6-Methyladenosine Regulators Contribute to Tumor Immune Microenvironment and Have Clinical Prognostic Impact in Breast Cancer

Frontiers in Genetics ◽

10.3389/fgene.2021.650499 ◽

2022 ◽

Vol 12 ◽

Author(s):

Lan-Xin Mu ◽

You-Cheng Shao ◽

Lei Wei ◽

Fang-Fang Chen ◽

Jing-Wei Zhang

Keyword(s):

Breast Cancer ◽

Immune Cell ◽

Risk Model ◽

Cox Regression ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Prognostic Impact ◽

Immune Microenvironment ◽

Model Based ◽

Tumor Immune Microenvironment

Purpose: This study aims to reveal the relationship between RNA N6-methyladenosine (m6A) regulators and tumor immune microenvironment (TME) in breast cancer, and to establish a risk model for predicting the occurrence and development of tumors.Patients and methods: In the present study, we respectively downloaded the transcriptome dataset of breast cancer from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database to analyze the mutation characteristics of m6A regulators and their expression profile in different clinicopathological groups. Then we used the weighted correlation network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO), and cox regression to construct a risk prediction model based on m6A-associated hub genes. In addition, Immune infiltration analysis and gene set enrichment analysis (GSEA) was used to evaluate the immune cell context and the enriched gene sets among the subgroups.Results: Compared with adjacent normal tissue, differentially expressed 24 m6A regulators were identified in breast cancer. According to the expression features of m6A regulators above, we established two subgroups of breast cancer, which were also surprisingly distinguished by the feature of the immune microenvironment. The Model based on modification patterns of m6A regulators could predict the patient’s T stage and evaluate their prognosis. Besides, the low m6aRiskscore group presents an immune-activated phenotype as well as a lower tumor mutation load, and its 5-years survival rate was 90.5%, while that of the high m6ariskscore group was only 74.1%. Finally, the cohort confirmed that age (p < 0.001) and m6aRiskscore (p < 0.001) are both risk factors for breast cancer in the multivariate regression.Conclusion: The m6A regulators play an important role in the regulation of breast tumor immune microenvironment and is helpful to provide guidance for clinical immunotherapy.

Download Full-text

BRAF Mutation as a Potential Therapeutic Target for Checkpoint Inhibitors: A Comprehensive Analysis of Immune Microenvironment in BRAF Mutated Colon Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.705060 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shuyi Cen ◽

Kun Liu ◽

Yu Zheng ◽

Jianzhen Shan ◽

Chao Jing ◽

...

Keyword(s):

Colon Cancer ◽

Braf Mutation ◽

Plasma Cells ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Immune Microenvironment ◽

Tissue Specimens

BRAF mutated colon cancer presents with poor survival, and the treatment strategies are controversial. The tumor microenvironment, which plays a key role in tumorigenesis as well as responses to treatments, of this subtype is largely unknown. In the present study, we analyzed the differences of immune microenvironments between BRAF mutated and BRAF wild-type colon cancer utilizing datasets from The Cancer Genome Atlas and Gene Expression Omnibus and confirmed the findings by tissue specimens of patients. We found that BRAF mutated colon cancer had more stromal cells, more immune cell infiltration, and lower tumor purity. Many immunotherapeutic targets, including PD-1, PD-L1, CTLA-4, LAG-3, and TIM-3, were highly expressed in BRAF mutated patients. BRAF mutation was also correlated with higher proportions of neutrophils and macrophages M1, and lower proportions of plasma cells, dendritic cells resting, and T cells CD4 naïve. In conclusion, our study demonstrates a different pattern of the immune microenvironment in BRAF mutated colon cancer and provides insights into the future use of checkpoint inhibitors in this subgroup of patients.

Download Full-text

Tumor Immune Microenvironment Related Gene-Based Model to Predict Prognosis and Response to Compounds in Ovarian Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.807410 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jiang Yang ◽

Shasha Hong ◽

Xiaoyi Zhang ◽

Jingchun Liu ◽

Ying Wang ◽

...

Keyword(s):

Ovarian Cancer ◽

Risk Score ◽

Immune Cell ◽

Cox Regression ◽

Killer Cell ◽

Figo Stage ◽

The Cancer Genome Atlas ◽

Immune Microenvironment ◽

Natural Killer Cell Cytotoxicity ◽

Tumor Immune Microenvironment

BackgroundThe tumor immune microenvironment (TIME) has been recognized to be an imperative factor facilitating the acquisition of many cancer-related hallmarks and is a critical target for targeted biological therapy. This research intended to construct a risk score model premised on TIME-associated genes for prediction of survival and identification of potential drugs for ovarian cancer (OC) patients.Methods and ResultsThe stromal and immune scores were computed utilizing the ESTIMATE algorithm in OC patient samples from The Cancer Genome Atlas (TCGA) database. Weighted gene co-expression network and differentially expressed genes analyses were utilized to detect stromal-and immune-related genes. The Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression was utilized for additional gene selection. The genes that were selected were utilized as the input for a stepwise regression to construct a TIME-related risk score (TIMErisk), which was then validated in Gene Expression Omnibus (GEO) database. For the evaluation of the protein expression levels of TIME regulators, the Human Protein Atlas (HPA) dataset was utilized, and for their biological functions, the TIMER and CIBERSORT algorithm, immunoreactivity, and Immune Cell Abundance Identifier (ImmuCellAI) were used. Possible OC medications were forecasted utilizing the Genomics of Drug Sensitivity in Cancer (GDSC) database and connectivity map (CMap). TIMErisk was developed based on ALPK2, CPA3, PTGER3, CTHRC1, PLA2G2D, CXCL11, and ZNF683. High TIMErisk was recognized as a poor factor for survival in the GEO and TCGA databases; subgroup analysis with FIGO stage, grade, lymphatic and venous invasion, debulking, and tumor site also indicated similar results. Functional immune cells corresponded to more incisive immune reactions, including secretion of chemokines and interleukins, natural killer cell cytotoxicity, TNF signaling pathway, and infiltration of activated NK cells, eosinophils, and neutrophils in patients with low TIMErisk. Several small molecular medications which may enhance the prognosis of patients in the TIMErisk subgroup were identified. Lastly, an enhanced predictive performance nomogram was constructed by compounding TIMErisk with the FIGO stage and debulking.ConclusionThese findings may offer a valuable indicator for clinical stratification management and personalized therapeutic options for OC patients and may be a foundation for future mechanistic research of their association.

Download Full-text

Integrative Analysis of Neuregulin Family Members-Related Tumor Microenvironment for Predicting the Prognosis in Gliomas

Frontiers in Immunology ◽

10.3389/fimmu.2021.682415 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wei-jiang Zhao ◽

Guan-yong Ou ◽

Wen-wen Lin

Keyword(s):

Prognostic Value ◽

Immune Cell ◽

Characteristic Curve ◽

Family Members ◽

The Cancer Genome Atlas ◽

Lower Grade ◽

Sequencing Data ◽

Immune Microenvironment ◽

Gene Set ◽

Tumor Immune Microenvironment

Gliomas, including brain lower grade glioma (LGG) and glioblastoma multiforme (GBM), are the most common primary brain tumors in the central nervous system. Neuregulin (NRG) family proteins belong to the epidermal growth factor (EGF) family of extracellular ligands and they play an essential role in both the central and peripheral nervous systems. However, roles of NRGs in gliomas, especially their effects on prognosis, still remain to be elucidated. In this study, we obtained raw counts of RNA-sequencing data and corresponding clinical information from 510 LGG and 153 GBM samples from The Cancer Genome Atlas (TCGA) database. We analyzed the association of NRG1-4 expression levels with tumor immune microenvironment in LGG and GBM. GSVA (Gene Set Variation Analysis) was performed to determine the prognostic difference of NRGs gene set between LGG and GBM. ROC (receiver operating characteristic) curve and the nomogram model were constructed to estimate the prognostic value of NRGs in LGG and GBM. The results demonstrated that NRG1-4 were differentially expressed in LGG and GBM in comparison to normal tissue. Immune score analysis revealed that NRG1-4 were significantly related to the tumor immune microenvironment and remarkably correlated with immune cell infiltration. The investigation of roles of m6A (N6-methyladenosine, m6A)-related genes in gliomas revealed that NRGs were prominently involved in m6A RNA modification. GSVA score showed that NRG family members are more associated with prognosis in LGG compared with GBM. Prognostic analysis showed that NRG3 and NRG1 can serve as potential independent biomarkers in LGG and GBM, respectively. Moreover, GDSC drug sensitivity analysis revealed that NRG1 was more correlated with drug response compared with other NRG subtypes. Based on these public databases, we preliminarily identified the relationship between NRG family members and tumor immune microenvironment, and the prognostic value of NRGs in gliomas. In conclusion, our study provides comprehensive roles of NRG family members in gliomas, supporting modulation of NRG signaling in the management of glioma.

Download Full-text

250 Spatial-transcriptomic analysis of tumor-immune microenvironment in AML patients receiving pembrolizumab and decitabine

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.250 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A270-A270

Author(s):

Chen Zhao ◽

Abigail Wong-Rolle ◽

Prajan Divakar ◽

Katherine Calvo ◽

Christopher Hourigan

Keyword(s):

T Cells ◽

T Cell ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Transcriptomic Analysis ◽

Inadequate Response ◽

Immune Microenvironment ◽

Clinical Center ◽

Tumor Immune Microenvironment ◽

Refractory Acute Myeloid Leukemia

BackgroundRelapsed or refractory Acute Myeloid Leukemia (R-AML) is a deadly disease with an inadequate response rate to current treatments. Recent advances in immunotherapy shed light on R-AML, and several clinical trials have shown promising potential for combining immune checkpoint inhibitors (ICIs) with hypomethylating agents. A deeper understanding of the tumor-immune microenvironment in R-AML during combination ICI treatment is urgently needed for developing better therapeutics and stratifying treatment strategies.MethodsTo dissect the tumor-immune interactions in the bone marrow microenvironment, we employed nanoString GeoMx Digital Spatial Profiler (DSP) and performed a spatial-transcriptomic analysis of patients with R-AML who received pembrolizumab and decitabine. We compared the transcriptomic profiles and TCR clonalities of tumor-interacting T cells, bystander T cells, and other cells at baseline, post-pembrolizumab treatment, and post-decitabine, which enable us to identify R-AML’s suppressive immune microenvironment and immune cells’ responses to ICI and hypomethylating agent.ResultsWe obtained the spatial-transcriptomic profiles of T cells, stromal cells, and leukemia cells in patients with R-AML at different treatment points. Our TCR-specific probes were able to track T cell clonal changes during treatments.ConclusionsR-AML harbored a complex tumor immune microenvironment and diverse T cell clonality.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NCI (the Center for Cancer Research), NHLBI, and NIH Clinical Center.Ethics ApprovalThis study is approved by NHLBI IRB.

Download Full-text

Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003032 ◽

2021 ◽

Vol 9 (9) ◽

pp. e003032

Author(s):

James Harber ◽

Tamihiro Kamata ◽

Catrin Pritchard ◽

Dean Fennell

Keyword(s):

Treatment Options ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Phase Iii ◽

Immune Microenvironment ◽

Incurable Cancer ◽

Phase Iii Clinical Trials ◽

Dismal Prognosis ◽

Tumor Immune Microenvironment ◽

Cancer Tumor

Malignant pleural mesothelioma (MPM) is an incurable cancer with a dismal prognosis and few effective treatment options. Nonetheless, recent positive phase III trial results for immune checkpoint blockade (ICB) in MPM herald a new dawn in the fight to advance effective treatments for this cancer. Tumor mutation burden (TMB) has been widely reported to predict ICB in other cancers, but MPM is considered a low-TMB tumor. Similarly, tumor programmed death-ligand 1 (PD-L1) expression has not been proven predictive in phase III clinical trials in MPM. Consequently, the precise mechanisms that determine response to immunotherapy in this cancer remain unknown. The present review therefore aimed to synthesize our current understanding of the tumor immune microenvironment in MPM and reflects on how specific cellular features might impact immunotherapy responses or lead to resistance. This approach will inform stratified approaches to therapy and advance immunotherapy combinations in MPM to improve clinical outcomes further.

Download Full-text

Intratumoral Adipocyte-High Breast Cancer Enrich for Metastatic and Inflammation-Related Pathways but Associated with Less Cancer Cell Proliferation

International Journal of Molecular Sciences ◽

10.3390/ijms21165744 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5744 ◽

Cited By ~ 8

Author(s):

Yoshihisa Tokumaru ◽

Masanori Oshi ◽

Eriko Katsuta ◽

Li Yan ◽

Jing Li Huang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Cancer Biology ◽

The Cancer Genome Atlas ◽

Related Gene ◽

Immune Microenvironment ◽

Gene Sets ◽

Tumor Immune Microenvironment ◽

Er Positive

Cancer-associated adipocytes are known to cause inflammation, leading to cancer progression and metastasis. The clinicopathological and transcriptomic data from 2256 patients with breast cancer were obtained based on three cohorts: The Cancer Genome Atlas (TCGA), GSE25066, and a study by Yau et al. For the current study, we defined the adipocyte, which is calculated by utilizing a computational algorithm, xCell, as “intratumoral adipocyte”. These intratumoral adipocytes appropriately reflected mature adipocytes in a bulk tumor. The amount of intratumoral adipocytes demonstrated no relationship with survival. Intratumoral adipocyte-high tumors significantly enriched for metastasis and inflammation-related gene sets and are associated with a favorable tumor immune microenvironment, especially in the ER+/HER2- subtype. On the other hand, intratumoral adipocyte-low tumors significantly enriched for cell cycle and cell proliferation-related gene sets. Correspondingly, intratumoral adipocyte-low tumors are associated with advanced pathological grades and inversely correlated with MKI67 expression. In conclusion, a high amount of intratumoral adipocytes in breast cancer was associated with inflammation, metastatic pathways, cancer stemness, and favorable tumor immune microenvironment. However, a low amount of adipocytes was associated with a highly proliferative tumor in ER-positive breast cancer. This cancer biology may explain the reason why patient survival did not differ by the amount of adipocytes.

Download Full-text

Rare and potentially pathogenic variants in hydroxycarboxylic acid receptor genes identified in breast cancer cases

BMC Medical Genomics ◽

10.1186/s12920-021-01126-3 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Cierla McGuire Sams ◽

Kasey Shepp ◽

Jada Pugh ◽

Madison R. Bishop ◽

Nancy D. Merner

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Treatment Strategies ◽

The Cancer Genome Atlas ◽

Acid Oxidation ◽

Loss Of Function ◽

Cancer Proliferation ◽

Hydroxycarboxylic Acid ◽

Pathogenic Variants

Abstract Background Three genes clustered together on chromosome 12 comprise a group of hydroxycarboxylic acid receptors (HCARs): HCAR1, HCAR2, and HCAR3. These paralogous genes encode different G-protein coupled receptors responsible for detecting glycolytic metabolites and controlling fatty acid oxidation. Though better known for regulating lipid metabolism in adipocytes, more recently, HCARs have been functionally associated with breast cancer proliferation/survival; HCAR2 has been described as a tumor suppressor and HCAR1 and HCAR3 as oncogenes. Thus, we sought to identify germline variants in HCAR1, HCAR2, and HCAR3 that could potentially be associated with breast cancer risk. Methods Two different cohorts of breast cancer cases were investigated, the Alabama Hereditary Cancer Cohort and The Cancer Genome Atlas, which were analyzed through nested PCRs/Sanger sequencing and whole-exome sequencing, respectively. All datasets were screened for rare, non-synonymous coding variants. Results Variants were identified in both breast cancer cohorts, some of which appeared to be associated with breast cancer BC risk, including HCAR1 c.58C > G (p.P20A), HCAR2 c.424C > T (p.R142W), HCAR2 c.517_518delinsAC (p.G173T), HCAR2 c.1036A > G (p.M346V), HCAR2 c.1086_1090del (p.P363Nfs*26), HCAR3 c.560G > A (p.R187Q), and HCAR3 c.1117delC (p.Q373Kfs*82). Additionally, HCAR2 c.515C > T (p.S172L), a previously identified loss-of-function variant, was identified. Conclusions Due to the important role of HCARs in breast cancer, it is vital to understand how these genetic variants play a role in breast cancer risk and proliferation and their consequences on treatment strategies. Additional studies will be needed to validate these findings. Nevertheless, the identification of these potentially pathogenic variants supports the need to investigate their functional consequences.

Download Full-text

Hyperion Image Analysis Depicts a Preliminary Landscape of Tumor Immune Microenvironment in OSCC with Lymph Node Metastasis

Journal of Immunology Research ◽

10.1155/2021/9975423 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Shang Xie ◽

Xin-Yuan Zhang ◽

Xiao-Feng Shan ◽

Vicky Yau ◽

Jian-Yun Zhang ◽

...

Keyword(s):

Lymph Node ◽

Lymph Node Metastasis ◽

Treatment Planning ◽

Immune Cell ◽

Imaging System ◽

Individual Treatment ◽

Immune Microenvironment ◽

Node Metastasis ◽

Tumor Immune Microenvironment ◽

Formalin Fixed Paraffin Embedded

Background. Oral squamous cell carcinoma (OSCC) constitutes the most common types of oral cancer. Because its prognosis varies significantly, identification of a tumor immune microenvironment could be a critical tool for treatment planning and predicting a more accurate prognosis. This study is aimed at utilizing the Hyperion imaging system to depict a preliminary landscape of the tumor immune microenvironment in OSCC with lymph node metastasis. Methods. We collected neoplasm samples from OSCC patients. Their formalin-fixed, paraffin-embedded (FFPE) tissue sections were obtained and stained utilizing a panel of 26 clinically relevant metal-conjugated antibodies. Detection and analysis were performed for these stained cells with the Hyperion imaging system. Results. Four patients met our inclusion criteria. We depicted a preliminary landscape of their tumor immune microenvironment and identified 25 distinct immune cell subsets from these OSCC patients based on phenotypic similarity. All these patients had decreased expression of CD8+ T cells in tumor specimens. Variety in cell subsets was seen, and more immune activated cells were found in patient A and patient B than those in patient C and patient D. Such differences in tumor immune microenvironments can contribute to forecasting of individual prognoses. Conclusion. The Hyperion imaging system helped to delineate a preliminary and multidimensional landscape of the tumor immune microenvironment in OSCC with lymph node metastasis and provided insights into the influence of the immune microenvironment in determination of prognoses. These results reveal possible contributory factors behind different prognoses of OSCC patients with lymph node metastasis and provide reference for individual treatment planning.

Download Full-text

CDKN2B-AS1 Promotes Malignancy as a Novel Prognosis-Related Molecular Marker in the Endometrial Cancer Immune Microenvironment

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.721676 ◽

2021 ◽

Vol 9 ◽

Author(s):

Di Yang ◽

Jian Ma ◽

Xiao-Xin Ma

Keyword(s):

Endometrial Cancer ◽

Immune Cell ◽

Quantitative Polymerase Chain Reaction ◽

Treatment Strategies ◽

Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Immune Infiltration ◽

Lncrna Expression ◽

Ec Cells

The prognosis of patients with endometrial cancer (EC) is closely associated with immune cell infiltration. Although abnormal long non-coding RNA (lncRNA) expression is also linked to poor prognosis in patients with EC, the function and action mechanism of immune infiltration-related lncRNAs underlying the occurrence and development of EC remains unclear. In this study, we analyzed lncRNA expression using The Cancer Genome Atlas and clinical data and identified six lncRNAs as prognostic markers for EC, all of which are associated with the infiltration of immune cell subtypes, as illustrated by ImmLnc database and ssGSEA analysis. Real-time quantitative polymerase chain reaction showed that CDKN2B-AS1 was significantly overexpressed in EC, whereas its knockdown inhibited the proliferation and invasion of EC cells and the in vivo growth of transplanted tumors in nude mice. Finally, we constructed a competing endogenous RNA regulatory network and conducted Gene Ontology enrichment analysis to elucidate the potential molecular mechanism underlying CDKN2B-AS1 function. Overall, we identified molecular targets associated with immune infiltration and prognosis and provide new insights into the development of molecular therapies and treatment strategies against EC.

Download Full-text