New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy

The majority of basic and clinical studies have shown a protumor function of tumor-associated macrophages (TAMs), which represent a large proportion of matrix cells. TAMs promote tumorigenesis, and their number is related to the malignancy degree and poor prognosis of many kinds of tumors. Macrophage plasticity makes it possible to change the tumor microenvironment and remodel antitumor immunity during cancer immunotherapy. Increasing numbers of studies have revealed the effects of TAMs on the tumor microenvironment, for example, via promotion of tumor growth and tumorigenesis and through an increase in the number of cancer stem cells or via facilitation of angiogenesis, lymphangiogenesis, and metastasis. Investigators also proposed tumor-immunological treatments targeting TAMs by inhibiting TAM recruitment and differentiation, by regulating TAM polarization, and by blocking factors and pathways associated with the protumor function of TAMs. This comprehensive review presents recent research on TAMs in relation to prediction of poor outcomes, remodeling of the tumor immune microenvironment, and immunological targeted therapies.

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Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001341 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001341

Author(s):

Chunxiao Li ◽

Xiaofei Xu ◽

Shuhua Wei ◽

Ping Jiang ◽

Lixiang Xue ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Cells ◽

Poor Prognosis ◽

Tumor Immunotherapy ◽

Therapeutic Strategies ◽

Preclinical Studies ◽

Future Prospects ◽

Tumor Associated Macrophages

Macrophages are the most important phagocytes in vivo. However, the tumor microenvironment can affect the function and polarization of macrophages and form tumor-associated macrophages (TAMs). Usually, the abundance of TAMs in tumors is closely associated with poor prognosis. Preclinical studies have identified important pathways regulating the infiltration and polarization of TAMs during tumor progression. Furthermore, potential therapeutic strategies targeting TAMs in tumors have been studied, including inhibition of macrophage recruitment to tumors, functional repolarization of TAMs toward an antitumor phenotype, and other therapeutic strategies that elicit macrophage-mediated extracellular phagocytosis and intracellular destruction of cancer cells. Therefore, with the increasing impact of tumor immunotherapy, new antitumor strategies to target TAMs are now being discussed.

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Characterizing the Tumor Immune Microenvironment with Tyramide-Based Multiplex Immunofluorescence

Journal of Mammary Gland Biology and Neoplasia ◽

10.1007/s10911-021-09479-2 ◽

2020 ◽

Vol 25 (4) ◽

pp. 417-432

Author(s):

Hidetoshi Mori ◽

Jennifer Bolen ◽

Louis Schuetter ◽

Pierre Massion ◽

Clifford C. Hoyt ◽

...

Keyword(s):

Tumor Microenvironment ◽

Multispectral Imaging ◽

Imaging System ◽

Predictive Biomarkers ◽

Cell Types ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Manual Processing ◽

Cell Densities ◽

Immune Profiling

AbstractMultiplex immunofluorescence (mIF) allows simultaneous antibody-based detection of multiple markers with a nuclear counterstain on a single tissue section. Recent studies have demonstrated that mIF is becoming an important tool for immune profiling the tumor microenvironment, further advancing our understanding of the interplay between cancer and the immune system, and identifying predictive biomarkers of response to immunotherapy. Expediting mIF discoveries is leading to improved diagnostic panels, whereas it is important that mIF protocols be standardized to facilitate their transition into clinical use. Manual processing of sections for mIF is time consuming and a potential source of variability across numerous samples. To increase reproducibility and throughput we demonstrate the use of an automated slide stainer for mIF incorporating tyramide signal amplification (TSA). We describe two panels aimed at characterizing the tumor immune microenvironment. Panel 1 included CD3, CD20, CD117, FOXP3, Ki67, pancytokeratins (CK), and DAPI, and Panel 2 included CD3, CD8, CD68, PD-1, PD-L1, CK, and DAPI. Primary antibodies were first tested by standard immunohistochemistry and single-plex IF, then multiplex panels were developed and images were obtained using a Vectra 3.0 multispectral imaging system. Various methods for image analysis (identifying cell types, determining cell densities, characterizing cell-cell associations) are outlined. These mIF protocols will be invaluable tools for immune profiling the tumor microenvironment.

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The effect of PEGylation on the efficacy and uptake of an immunostimulatory nanoparticle in the tumor immune microenvironment

Nanoscale Advances ◽

10.1039/d1na00308a ◽

2021 ◽

Author(s):

Wyatt M. Becicka ◽

Peter Bielecki ◽

Morgan Lorkowski ◽

Taylor J. Moon ◽

Yahan Zhang ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Immunosuppressive Tumor Microenvironment

The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells. To reprogram the tumor-resident innate immune cells, we developed an...

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RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4+ T-cell-dependent antitumor immunity

Nature Cancer ◽

10.1038/s43018-021-00263-z ◽

2021 ◽

Vol 2 (10) ◽

pp. 1018-1038

Author(s):

Zhuo Zhang ◽

Lin Luo ◽

Chuan Xing ◽

Yu Chen ◽

Peng Xu ◽

...

Keyword(s):

T Cell ◽

Antitumor Immunity ◽

Cd4 T Cell ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment

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Characterization of the Tumor Immune Microenvironment in Lung Squamous Cell Carcinoma Using Imaging Mass Cytometry

Frontiers in Oncology ◽

10.3389/fonc.2021.620989 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ran Li ◽

Ying Lin ◽

Yu Wang ◽

Shaoyuan Wang ◽

Yang Yang ◽

...

Keyword(s):

Immune Response ◽

Squamous Cell Carcinoma ◽

T Cells ◽

Tumor Microenvironment ◽

Lung Squamous Cell Carcinoma ◽

Mass Cytometry ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Tumor Region ◽

Proinflammatory Role

BackgroundLung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer. The tumor immune microenvironment (TIME) affects the anti-tumor immune response and the patient’s prognosis, although the TIME in LUSC patients is incompletely understood.MethodsWe retrospectively collected surgical specimens from patients with previously untreated primary LUSC. Histopathological examination was used to identify tumor regions and adjacent regions, and imaging mass cytometry was used to characterize the immune cells in those regions. The results were compared between regions and between patients.ResultsWe identified heterogeneity in the TIME on comparing different patients with LUSC, although the tumor region and adjacent region both exhibited an immune response to the tumor. The TIME typically included a large number of infiltrating and activated T-cells, especially CD8+ T-cells, which closely interacted with the tumor cells in the tumor region. There was limited infiltration of B-cells, NK cells, and NKT cells, while the major immune suppressor cells were CD33+ myeloid-derived cells. We also identified a novel population of CD3−CD4+ cells with high expression of Foxp3 and TNFα, which might modulate the tumor microenvironment and play a proinflammatory role in the TIME.ConclusionsThe TIME of LUSC appears to be immunogenic and heterogenous, with predominant infiltration of activated CD8+ T-cells. The interactions between the tumor cells and T-cells facilitate the anti-tumor activity. A novel subpopulation of CD3−CD4+ cells with high TNFα and Foxp3 expression may modulate the tumor microenvironment and play a proinflammatory role.

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Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

10.21203/rs.3.rs-257705/v2 ◽

2021 ◽

Author(s):

Inga-Maria Launonen ◽

Nuppu Lyytikäinen ◽

Julia Casado ◽

Ella Anttila ◽

Angéla Szabó ◽

...

Keyword(s):

Tumor Microenvironment ◽

Single Cell ◽

Single Cells ◽

High Grade ◽

Prognostic Role ◽

Immune Microenvironment ◽

Proteomic Data ◽

Tumor Immune Microenvironment ◽

Cellular Phenotypes

Abstract The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generated spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes (HRwt). We identified a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we found an opposing prognostic role of a proliferative tumor-cell phenotypic subpopulation in the HR-genotypes, which associated with enhanced spatial tumor-immune interactions by the CD8+ and CD4+T-cells in BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the premise to improve immunotherapeutic strategies and patient stratification in HGSC.

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Significance of CD47 and Its Association With Tumor Immune Microenvironment Heterogeneity in Ovarian Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.768115 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lan Yu ◽

Yi Ding ◽

Ting Wan ◽

Ting Deng ◽

He Huang ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Single Cell ◽

Prognostic Biomarker ◽

Gene Set Enrichment Analysis ◽

Cancer Prognosis ◽

Expression Level ◽

Immune Microenvironment ◽

Immune Infiltration ◽

Tumor Immune Microenvironment

BackgroundIt was reported that tumor heterogeneity and the surrounding tumor microenvironment (TME) in ovarian cancer affects immunotherapy efficacy and patient outcomes. And the TME of ovarian cancer is intrinsically heterogeneous. CD47 plays vital roles in cell functional behavior and immune homeostasis relating to cancer prognosis. But how it affects TME and its contribution to heterogeneity in ovarian cancer has not been fully illustrated. Therefore, we aimed to identify a prognostic biomarker which may help explain tumor immune microenvironment heterogeneity of ovarian cancer.MethodsCancer single-cell state atlas (CancerSEA) was used to evaluate functional role of CD47. Several bioinformatics database including Oncomine, Gene Expression Profiling Interaction Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), The Human Protein Atlas (HPA), Ualcan and Kaplan-Meier plotter (KM plotter) were applied to illustrate correlation of CD47 with ovarian cancer prognosis and immune infiltration. Tumor Immune Single-cell Hub (TISCH) single cell database was employed to evaluate correlation of CD47 with tumor microenvironment. GeneMANIA was implemented to identify regulation networks of CD47. Differentially expressed genes (DEGs) between CD47 high and low expression groups were analyzed with R package DESeq2. Kyoto encyclopedia of genes and genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were utilized to explore how CD47 affect the immune related cell signaling pathway.ResultsCD47 expression was upregulated and connected to worse OS and PFS in ovarian cancer. Close relation was found between CD47 expression level and immune infiltration in ovarian cancer, especially with Treg cells, Monocytes, Macrophages and T cell exhaustion (P<0.05). The CD47 expression level was relatively low in plasma cells, dendritic cells and Mono/Macro cells of OV_GSE115007, in myofibroblasts, fibroblasts and endothelial cells of OV_GSE118828, compared to malignant cells of OV_GSE118828 dataset. The cell components and distribution in primary and metastatic ovarian cancer are quite distinct, which may lead to TME heterogeneity of ovarian cancer.ConclusionOur results indicated that CD47 is closely correlated to ovarian cancer immune microenvironment and might induce ovarian cancer heterogeneity. Therefore, CD47 may be used as a candidate prognostic biomarker and provide us with new insights into potential immunotherapy in ovarian cancer patients.

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A Hypoxia Gene-Based Signature to Predict the Survival and Affect the Tumor Immune Microenvironment of Osteosarcoma in Children

Journal of Immunology Research ◽

10.1155/2021/5523832 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Feng Jiang ◽

Xiao-Lin Miao ◽

Xiao-Tian Zhang ◽

Feng Yan ◽

Yan Mao ◽

...

Keyword(s):

High Risk ◽

Poor Prognosis ◽

Gene Signature ◽

Response Strength ◽

Gene Expression Omnibus ◽

Immune Microenvironment ◽

Prognostic Predictor ◽

Molecular Features ◽

Tumor Immune Microenvironment ◽

Immunosuppressive Microenvironment

Osteosarcoma is a quickly developing, malignant cancer of the bone, which is associated with a bad prognosis. In osteosarcoma, hypoxia promotes the malignant phenotype, which results in a cascade of immunosuppressive processes, poor prognosis, and a high risk of metastasis. Nonetheless, additional methodologies for the study of hyperoxia in the tumor microenvironment also need more analysis. We obtained 88 children patients with osteosarcoma from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and 53 children patients with RNA sequence and clinicopathological data from the Gene Expression Omnibus (GEO). We developed a four-gene signature related to hypoxia to reflect the immune microenvironment in osteosarcoma that predicts survival. A high-risk score indicated a poor prognosis and immunosuppressive microenvironment. The presence of the four-gene signature related to hypoxia was correlated with clinical and molecular features and was an important prognostic predictor for pediatric osteosarcoma patients. In summary, we established and validated a four-gene signature related to hypoxia to forecast recovery and presented an independent prognostic predictor representing overall immune response strength within the osteosarcoma microenvironment.

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Pan-Cancer Prognostic, Immunity, Stemness, and Anticancer Drug Sensitivity Characterization of N6-Methyladenosine RNA Modification Regulators in Human Cancers

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.644620 ◽

2021 ◽

Vol 8 ◽

Author(s):

Rui Li ◽

Yun-Hong Yin ◽

Xiu-Li Ji ◽

Xiao Liu ◽

Jian-Ping Li ◽

...

Keyword(s):

Tumor Microenvironment ◽

Anticancer Drug ◽

Drug Sensitivity ◽

Rna Modification ◽

Immune Microenvironment ◽

Normal Tissues ◽

Tumor Immune Microenvironment ◽

Cancer Types ◽

Pan Cancer

N6-methyladenosine RNA modification plays a significant role in the progression of multiple tumorigenesis. Our study identified the imperative role of m6A regulators in the tumor immune microenvironment, survival, stemness score, and anticancer drug sensitivity of pan-cancer. The Wilcox test was to identify the differential expression between 17 m6A regulators across 33 TCGA cancer types and their normal tissues from UCSC Xena GDC pan-cancer. Survival analysis of m6A-related regulators in 33 TCGA cancer types was identified using the “survival” and “survminer” package. The Spearman correlation test and Pearson correlation test were used to identify the correlation relationship between m6A regulators expression and tumor microenvironment, tumor stem cell score, and drug sensitivity of anticancer drugs. ConsensusPathDB was used for exploring m6A regulators functional enrichment. The 17 (METTL3, WTAP, METTL14, RBM15, RBM15B, VIRMA, HNRNPC, HNRNPA2B1, YTHDC1, ZC3H13, YTHDF1, YTHDC2, YTHDF2, IGF2BP3, IGF2BP1, FTO, and ALKBH5) m6A regulators were differentially expressed in 18 TCGA cancer types and adjacent normal tissues. Correlation analysis indicated that the relationship between the expression of 17 m6A regulators and tumor microenvironment indicated that the higher expression of m6A regulators, the higher the degree of tumor stem cells. The anticancer drug sensitivity analysis indicated that ZC3H13 expression had a positive relationship with anticancer drugs such as selumetinib, dabrafenib, cobimetinib, trametinib, and hypothemycin (p < 0.001). YTHDF2 expression was significantly negatively correlated with the anticancer drug dasatinib (p < 0.001). The pan-cancer immune subtype analysis showed that the 17 m6A regulators were significantly different in immune subtype C1 (wound healing), C3 (inflammatory), C2 (IFN-gamma dominant), C5 (immunological quiet), C4 (lymphocyte depleted), and C6 (TGF-beta dominant) (p < 0.001). Our study provides a comprehensive insight for revealing the significant role of m6A regulators in the tumor immune microenvironment, stemness score, and anticancer drug sensitivity of human cancers.

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Characterization of the m6A-Associated Tumor Immune Microenvironment in Prostate Cancer to Aid Immunotherapy

Frontiers in Immunology ◽

10.3389/fimmu.2021.735170 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zezhen Liu ◽

Jiehui Zhong ◽

Jie Zeng ◽

Xiaolu Duan ◽

Jianming Lu ◽

...

Keyword(s):

Prostate Cancer ◽

Poor Prognosis ◽

Response Rate ◽

Checkpoint Inhibitors ◽

Cell Infiltration ◽

Intratumor Heterogeneity ◽

Immune Microenvironment ◽

Th2 Cell ◽

Tumor Immune Microenvironment

The aim of this study was to elucidate the correlation between m6A modification and the tumor immune microenvironment (TIME) in prostate cancer (PCa) and to identify the m6A regulation patterns suitable for immune checkpoint inhibitors (ICIs) therapy. We evaluated the m6A regulation patterns of PCa based on 24 m6A regulators and correlated these modification patterns with TIME characteristics. Three distinct m6A regulation patterns were determined in PCa. The m6A regulators cluster with the best prognosis had significantly increased METTL14 and ZC3H13 expression and was characterized by low mutation rate, tumor heterogeneity, and neoantigens. The m6A regulators cluster with a poor prognosis had markedly high KIAA1429 and HNRNPA2B1 expression and was characterized by high intratumor heterogeneity and Th2 cell infiltration, while low Th17 cell infiltration and Macrophages M1/M2. The m6Ascore was constructed to quantify the m6A modification pattern of individual PCa patients based on m6A-associated genes. We found that the low-m6Ascore group with poor prognosis had a higher immunotherapeutic response rate than the high-m6Ascore group. The low-m6Ascore group was more likely to benefit from ICIs therapy. This study was determined that immunotherapy is more effective in low-m6Ascore PCa patients with poor prognosis.

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