An Independent Poor-Prognosis Subtype Synthesized Single-Sample mRNA Molecular Classification in Tumor Microenvironment of Bladder Cancer

Kinesin family member C1 (KIFC1), a minus end-directed motor protein, is reported to play an essential role in cancer. This study aimed to analyze KIFC1 expression and examine KIFC1 involvement in cisplatin resistance in bladder cancer (BC). Immunohistochemistry showed that 37 of 78 (47.4%) BC cases were positive for KIFC1. KIFC1-positive cases were associated with high T stage and lymph node metastasis. Kaplan-Meier analysis showed that KIFC1-positive cases were associated with poor prognosis, consistent with the results from public databases. Molecular classification in several public databases indicated that KIFC1 expression was increased in basal type BC. Immunohistochemistry showed that KIFC1-positive cases were associated with basal markers 34βE12, CK5 and CD44. KIFC1 expression was increased in altered TP53 compared to that in wild-type TP53. Immunohistochemistry showed that KIFC1-positive cases were associated with p53-positive cases. P53 knockout by CRISPR-Cas9 induced KIFC1 expression in BC cell lines. Knockdown of KIFC1 by siRNA increased the sensitivity to cisplatin in BC cells. Kaplan-Meier analysis indicated that prognosis was poor among KIFC1-positive BC patients treated with cisplatin-based chemotherapy. Immunohistochemistry showed that KIFC1-positive cases were associated with PD-L1-positive cases. High KIFC1 expression was associated with a favorable prognosis in patients treated with atezolizumab from the IMvigor 210 study. These results suggest that KIFC1 might be a promising biomarker and therapeutic target in BC.

Download Full-text

Recruitment and Expansion of Tregs Cells in the Tumor Environment—How to Target Them?

Cancers ◽

10.3390/cancers13081850 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1850

Author(s):

Justine Cinier ◽

Margaux Hubert ◽

Laurie Besson ◽

Anthony Di Roio ◽

Céline Rodriguez ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Tumor Microenvironment ◽

Poor Prognosis ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Major Function ◽

Normal Tissues ◽

Tumor Environment ◽

Plastic Transformation

Regulatory T cells (Tregs) are present in a large majority of solid tumors and are mainly associated with a poor prognosis, as their major function is to inhibit the antitumor immune response contributing to immunosuppression. In this review, we will investigate the mechanisms involved in the recruitment, amplification and stability of Tregs in the tumor microenvironment (TME). We will also review the strategies currently developed to inhibit Tregs’ deleterious impact in the TME by either inhibiting their recruitment, blocking their expansion, favoring their plastic transformation into other CD4+ T-cell subsets, blocking their suppressive function or depleting them specifically in the TME to avoid severe deleterious effects associated with Treg neutralization/depletion in the periphery and normal tissues.

Download Full-text

The Tumor Microenvironment and Immunotherapy in Prostate and Bladder Cancer

Urologic Clinics of North America ◽

10.1016/j.ucl.2020.10.005 ◽

2020 ◽

Vol 47 (4) ◽

pp. e17-e54

Author(s):

Sujit S. Nair ◽

Rachel Weil ◽

Zachary Dovey ◽

Avery Davis ◽

Ashutosh K. Tewari

Keyword(s):

Bladder Cancer ◽

Tumor Microenvironment

Download Full-text

Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

Genome Medicine ◽

10.1186/s13073-021-00931-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Clément Meiller ◽

François Montagne ◽

Theo Z. Hirsch ◽

Stefano Caruso ◽

Julien de Wolf ◽

...

Keyword(s):

Tumor Microenvironment ◽

Malignant Pleural Mesothelioma ◽

Tumor Heterogeneity ◽

Immunological Synapse ◽

Side Wall ◽

Molecular Classification ◽

Suppressor Gene ◽

Pleural Mesothelioma ◽

Sequencing Analysis ◽

Methylome Analysis

Abstract Background Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.

Download Full-text

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.

Download Full-text

Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis

Cancers ◽

10.3390/cancers13040733 ◽

2021 ◽

Vol 13 (4) ◽

pp. 733

Author(s):

Nobutaka Ebata ◽

Masashi Fujita ◽

Shota Sasagawa ◽

Kazuhiro Maejima ◽

Yuki Okawa ◽

...

Keyword(s):

Tumor Microenvironment ◽

Gallbladder Cancer ◽

Epithelial To Mesenchymal Transition ◽

Molecular Classification ◽

Mesenchymal Transition ◽

Elevated Expression ◽

Fresh Frozen ◽

Therapeutic Decision Making

Gallbladder cancer (GBC), a rare but lethal disease, is often diagnosed at advanced stages. So far, molecular characterization of GBC is insufficient, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. We performed a transcriptome analysis of both coding and non-coding RNAs from 36 GBC fresh-frozen samples. The results were integrated with those of comprehensive mutation profiling based on whole-genome or exome sequencing. The clustering analysis of RNA-seq data facilitated the classification of GBCs into two subclasses, characterized by high or low expression levels of TME (tumor microenvironment) genes. A correlation was observed between gene expression and pathological immunostaining. TME-rich tumors showed significantly poor prognosis and higher recurrence rate than TME-poor tumors. TME-rich tumors showed overexpression of genes involved in epithelial-to-mesenchymal transition (EMT) and inflammation or immune suppression, which was validated by immunostaining. One non-coding RNA, miR125B1, exhibited elevated expression in stroma-rich tumors, and miR125B1 knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed TP53 (47%) as the most commonly mutated gene, followed by ELF3 (13%) and ARID1A (11%). Mutations of ARID1A, ERBB3, and the genes related to the TGF-β signaling pathway were enriched in TME-rich tumors. This comprehensive analysis demonstrated that TME, EMT, and TGF-β pathway alterations are the main drivers of GBC and provides a new classification of GBCs that may be useful for therapeutic decision-making.

Download Full-text

Hypoxia and the Tumor Microenvironment

Technology in Cancer Research & Treatment ◽

10.1177/15330338211036304 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110363

Author(s):

Yue Li ◽

Long Zhao ◽

Xiao-Feng Li

Keyword(s):

Immune Response ◽

Cell Proliferation ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Poor Prognosis ◽

Tumor Biology ◽

Metastatic Potential ◽

Tumor Detection ◽

Tumor Aggressiveness

Hypoxia is an important feature of the tumor microenvironment, and is closely associated with cell proliferation, angiogenesis, metabolism and the tumor immune response. All these factors can further promote tumor progression, increase tumor aggressiveness, enhance tumor metastatic potential and lead to poor prognosis. In this review, these effects of hypoxia on tumor biology will be discussed, along with their significance for tumor detection and treatment.

Download Full-text

Treatment of solid tumors using bispecific anti-PDL-1/ICOS antibody

Pharmaceutical Patent Analyst ◽

10.4155/ppa-2020-0035 ◽

2021 ◽

Author(s):

Martin Perez-Santos ◽

Maricruz Anaya-Ruiz ◽

Gabriela Sanchez-Esgua ◽

Luis Villafaña-Diaz ◽

Diana Barron-Villaverde

Keyword(s):

Clinical Trials ◽

T Cells ◽

Tumor Microenvironment ◽

Cancer Treatment ◽

Potential Application ◽

Poor Prognosis ◽

Bispecific Antibody ◽

Control Points ◽

Immune Control ◽

Ct26 Model

PD-L1 and ICOS are immune control points in cancer and their presence in cancer tends to have a poor prognosis. WO2019122882 patent describes a bispecific antibody that targets PDL-1/ICOS with the potential application of cancer treatment. WO2019122882 patent describes a bispecific antibody with antitumor efficacy in CT26 model through of the depletion of TReg cells and improved ratio of CD8+ T cells: TReg in tumor microenvironment. The anti-PDL-1/ICOS antibody is new; however, only preclinical assays are shown using colon carcinoma model. So far, there are no reports of clinical trials to evaluate the safety, toxicity and efficacy, but it will be of great interest to analyze in the future if this antibody surpasses the action of the combinatorial therapy in cancer.

Download Full-text