An immunotherapeutic approach to decipher the role of long non-coding RNAs in cancer progression, resistance and epigenetic regulation of immune cells

AbstractImmunotherapeutic treatments are gaining attention due to their effective anti-tumor response. Particularly, the revolution of immune checkpoint inhibitors (ICIs) produces promising outcomes for various cancer types. However, the usage of immunotherapy is limited due to its low response rate, suggesting that tumor cells escape the immune surveillance. Rapid advances in transcriptomic profiling have led to recognize immune-related long non-coding RNAs (LncRNAs), as regulators of immune cell-specific gene expression that mediates immune stimulatory as well as suppression of immune response, indicating LncRNAs as targets to improve the efficacy of immunotherapy against tumours. Moreover, the immune-related LncRNAs acting as epigenetic modifiers are also under deep investigation. Thus, herein, is a summarised knowledge of LncRNAs and their regulation in the adaptive and innate immune system, considering their importance in autophagy and predicting putative immunotherapeutic responses.

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Cancer-Associated Fibroblasts in Oral Cancer: A Current Perspective on Function and Potential for Therapeutic Targeting

Frontiers in Oral Health ◽

10.3389/froh.2021.686337 ◽

2021 ◽

Vol 2 ◽

Author(s):

Kamila J. Bienkowska ◽

Christopher J. Hanley ◽

Gareth J. Thomas

Keyword(s):

Oral Cancer ◽

Cancer Progression ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Tumour Microenvironment ◽

Cancer Associated Fibroblasts ◽

Current Perspective ◽

And Function ◽

Exciting Development

The role of the tumour microenvironement (TME) in cancer progression and resistance to therapies is now widely recognized. The most prominent non-immune cell type in the microenvironment of oral cancer (OSCC) is cancer-associated fibroblasts (CAF). Although CAF are a poorly characterised and heterogenous cell population, those with an “activated” myofibroblastic phenotype have been shown to support OSCC progression, promoting growth, invasion and numerous other “hallmarks of malignancy.” CAF also confer broad resistance to different types of therapy, including chemo/radiotherapy and EGFR inhibitors; consistent with this, CAF-rich OSCC are associated with poor prognosis. In recent years, much CAF research has focused on their immunological role in the tumour microenvironment, showing that CAF shield tumours from immune attack through multiple mechanisms, and particularly on their role in promoting resistance to anti-PD-1/PD-L1 checkpoint inhibitors, an exciting development for the treatment of recurrent/metastatic oral cancer, but which fails in most patients. This review summarises our current understanding of CAF subtypes and function in OSCC and discusses the potential for targeting these cells therapeutically.

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STAT3, a Master Regulator of Anti-Tumor Immune Response

Cancers ◽

10.3390/cancers11091280 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1280 ◽

Cited By ~ 19

Author(s):

Rébé ◽

Ghiringhelli

Keyword(s):

Cancer Progression ◽

Immune Cells ◽

Cell Function ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Cancer Growth ◽

Signal Transducer ◽

Immune Cell Function ◽

Transcription 3

Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on the role of STAT3 and its regulation, e.g. by phosphorylation or acetylation in immune cells and how it might impact immune cell function and tumor progression. Moreover, we will review the ability of STAT3 to regulate checkpoint inhibitors.

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miR-205 in Breast Cancer: State of the Art

International Journal of Molecular Sciences ◽

10.3390/ijms22010027 ◽

2020 ◽

Vol 22 (1) ◽

pp. 27

Author(s):

Ilaria Plantamura ◽

Alessandra Cataldo ◽

Giulia Cosentino ◽

Marilena V. Iorio

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Normal Breast ◽

Response To Therapy ◽

Aberrant Expression ◽

Open Questions ◽

Tumor Tissues ◽

Breast Physiology ◽

Cancer Types

Despite its controversial roles in different cancer types, miR-205 has been mainly described as an oncosuppressive microRNA (miRNA), with some contrasting results, in breast cancer. The role of miR-205 in the occurrence or progression of breast cancer has been extensively studied since the first evidence of its aberrant expression in tumor tissues versus normal counterparts. To date, it is known that the expression of miR-205 in the different subtypes of breast cancer is decreasing from the less aggressive subtype, estrogen receptor/progesterone receptor positive breast cancer, to the more aggressive, triple negative breast cancer, influencing metastasis capability, response to therapy and patient survival. In this review, we summarize the most important discoveries that have highlighted the functional role of this miRNA in breast cancer initiation and progression, in stemness maintenance, in the tumor microenvironment, its potential role as a biomarker and its relevance in normal breast physiology—the still open questions. Finally, emerging evidence reveals the role of some lncRNAs in breast cancer progression as sponges of miR-205. Here, we also reviewed the studies in this field.

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Non-Coding RNAs as Prognostic Markers for Endometrial Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22063151 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3151 ◽

Cited By ~ 2

Author(s):

Roberto Piergentili ◽

Simona Zaami ◽

Anna Franca Cavaliere ◽

Fabrizio Signore ◽

Giovanni Scambia ◽

...

Keyword(s):

Endometrial Cancer ◽

Prognostic Markers ◽

Classification Systems ◽

Prognostic Role ◽

Protein Coding ◽

Pathological Characteristics ◽

Epigenetic Events ◽

Cancer Types ◽

Non Coding Rnas

Endometrial cancer (EC) has been classified over the years, for prognostic and therapeutic purposes. In recent years, classification systems have been emerging not only based on EC clinical and pathological characteristics but also on its genetic and epigenetic features. Noncoding RNAs (ncRNAs) are emerging as promising markers in several cancer types, including EC, for which their prognostic value is currently under investigation and will likely integrate the present prognostic tools based on protein coding genes. This review aims to underline the importance of the genetic and epigenetic events in the EC tumorigenesis, by expounding upon the prognostic role of ncRNAs.

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Role of the NUDT Enzymes in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22052267 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2267

Author(s):

Roni H. G. Wright ◽

Miguel Beato

Keyword(s):

Breast Cancer ◽

Signaling Pathways ◽

Cancer Progression ◽

Breast Cancers ◽

Metastatic Colonization ◽

Hormone Receptor Positive ◽

Aggressive Cancer ◽

Cancer Types ◽

Metastatic Process

Despite global research efforts, breast cancer remains the leading cause of cancer death in women worldwide. The majority of these deaths are due to metastasis occurring years after the initial treatment of the primary tumor and occurs at a higher frequency in hormone receptor-positive (Estrogen and Progesterone; HR+) breast cancers. We have previously described the role of NUDT5 (Nudix-linked to moiety X-5) in HR+ breast cancer progression, specifically with regards to the growth of breast cancer stem cells (BCSCs). BCSCs are known to be the initiators of epithelial-to-mesenchyme transition (EMT), metastatic colonization, and growth. Therefore, a greater understanding of the proteins and signaling pathways involved in the metastatic process may open the door for therapeutic opportunities. In this review, we discuss the role of NUDT5 and other members of the NUDT family of enzymes in breast and other cancer types. We highlight the use of global omics data based on our recent phosphoproteomic analysis of progestin signaling pathways in breast cancer cells and how this experimental approach provides insight into novel crosstalk mechanisms for stratification and drug discovery projects aiming to treat patients with aggressive cancer.

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Roles of Extracellular HSPs as Biomarkers in Immune Surveillance and Immune Evasion

International Journal of Molecular Sciences ◽

10.3390/ijms20184588 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4588 ◽

Cited By ~ 23

Author(s):

Eman A. Taha ◽

Kisho Ono ◽

Takanori Eguchi

Keyword(s):

Heat Shock ◽

Tumor Cells ◽

Cancer Progression ◽

Immune Evasion ◽

Checkpoint Inhibitors ◽

Membrane Surface ◽

Immune Surveillance ◽

Heat Shock Factor 1 ◽

Heterochromatin Protein 1 ◽

Liquid Biopsies

Extracellular heat shock proteins (ex-HSPs) have been found in exosomes, oncosomes, membrane surfaces, as well as free HSP in cancer and various pathological conditions, also known as alarmins. Such ex-HSPs include HSP90 (α, β, Gp96, Trap1), HSP70, and large and small HSPs. Production of HSPs is coordinately induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), while matrix metalloproteinase 3 (MMP-3) and heterochromatin protein 1 are novel inducers of HSPs. Oncosomes released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP) by which immune evasion can be established. The concepts of RASP are: (i) releases of ex-HSP and HSP-rich oncosomes are essential in RASP, by which molecular co-transfer of HSPs with oncogenic factors to recipient cells can promote cancer progression and resistance against stresses such as hypoxia, radiation, drugs, and immune systems; (ii) RASP of tumor cells can eject anticancer drugs, targeted therapeutics, and immune checkpoint inhibitors with oncosomes; (iii) cytotoxic lipids can be also released from tumor cells as RASP. ex-HSP and membrane-surface HSP (mHSP) play immunostimulatory roles recognized by CD91+ scavenger receptor expressed by endothelial cells-1 (SREC-1)+ Toll-like receptors (TLRs)+ antigen-presenting cells, leading to antigen cross-presentation and T cell cross-priming, as well as by CD94+ natural killer cells, leading to tumor cytolysis. On the other hand, ex-HSP/CD91 signaling in cancer cells promotes cancer progression. HSPs in body fluids are potential biomarkers detectable by liquid biopsies in cancers and tissue-damaged diseases. HSP-based vaccines, inhibitors, and RNAi therapeutics are also reviewed.

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Targeting KRAS: The Elephant in the Room of Epithelial Cancers

Frontiers in Oncology ◽

10.3389/fonc.2021.638360 ◽

2021 ◽

Vol 11 ◽

Author(s):

Valeria Merz ◽

Marina Gaule ◽

Camilla Zecchetto ◽

Alessandro Cavaliere ◽

Simona Casalino ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Small Cell Lung ◽

Synthetic Lethal ◽

Adaptive Resistance ◽

Epithelial Cancers ◽

Combination Strategies ◽

Downstream Effectors ◽

Cancer Types ◽

Direct Targeting

Mutations of the proto-oncogene KRAS are the most frequent gain-of-function alterations found in cancer. KRAS is mutated in about 30% of all human tumors, but it could reach more than 90% in certain cancer types such as pancreatic adenocarcinoma. Although historically considered to be undruggable, a particular KRAS mutation, the G12C variant, has recently emerged as an actionable alteration especially in non-small cell lung cancer (NSCLC). KRASG12C and pan-KRAS inhibitors are being tested in clinical trials and have recently shown promising activity. Due to the difficulties in direct targeting of KRAS, other approaches are being explored. The inhibition of target upstream activators or downstream effectors of KRAS pathway has shown to be moderately effective given the evidence of emerging mechanisms of resistance. Various synthetic lethal partners of KRAS have recently being identified and the inhibition of some of those might prove to be successful in the future. The study of escape mechanisms to KRAS inhibition could support the utility of combination strategies in overcoming intrinsic and adaptive resistance and enhancing clinical benefit of KRASG12C inhibitors. Considering the role of the microenvironment in influencing tumor initiation and promotion, the immune tumor niche of KRAS mutant tumors has been deeply explored and characterized for its unique immunosuppressive skewing. However, a number of aspects remains to be fully understood, and modulating this tumor niche might revert the immunoresistance of KRAS mutant tumors. Synergistic associations of KRASG12C and immune checkpoint inhibitors are being tested.

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Artificial intelligence-aided clinical annotation of a large multi-cancer genomic dataset

Nature Communications ◽

10.1038/s41467-021-27358-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kenneth L. Kehl ◽

Wenxin Xu ◽

Alexander Gusev ◽

Ziad Bakouny ◽

Toni K. Choueiri ◽

...

Keyword(s):

Cancer Progression ◽

Language Processing ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Precision Oncology ◽

Free Survival ◽

Clinical Endpoints ◽

Mutation Burden ◽

Clinical Annotation ◽

Cancer Types

AbstractTo accelerate cancer research that correlates biomarkers with clinical endpoints, methods are needed to ascertain outcomes from electronic health records at scale. Here, we train deep natural language processing (NLP) models to extract outcomes for participants with any of 7 solid tumors in a precision oncology study. Outcomes are extracted from 305,151 imaging reports for 13,130 patients and 233,517 oncologist notes for 13,511 patients, including patients with 6 additional cancer types. NLP models recapitulate outcome annotation from these documents, including the presence of cancer, progression/worsening, response/improvement, and metastases, with excellent discrimination (AUROC > 0.90). Models generalize to cancers excluded from training and yield outcomes correlated with survival. Among patients receiving checkpoint inhibitors, we confirm that high tumor mutation burden is associated with superior progression-free survival ascertained using NLP. Here, we show that deep NLP can accelerate annotation of molecular cancer datasets with clinically meaningful endpoints to facilitate discovery.

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Dysregulation of miRNA in cancer progression

10.31219/osf.io/u429y ◽

2021 ◽

Author(s):

Rucha P.

Keyword(s):

Gene Regulation ◽

Cancer Progression ◽

Therapeutic Target ◽

Chromosomal Abnormalities ◽

Human Cancer ◽

Epigenetic Modification ◽

Therapeutic Applications ◽

Non Coding Rnas ◽

Transcriptional Gene Regulation

MicroRNAs (miRNAs) are a category of highly conserved tiny non-coding RNAs that play a role in post-transcriptional gene regulation. Numerous studies have shown the role of dysregulated miRNA in a variety of illnesses, including human cancer. MiRNA is dysregulated by a variety of processes, including dysregulation of miRNA synthesis, aberrant miRNA transcription, dysregulated epigenetic modification, and chromosomal abnormalities. MiRNAs that are overexpressed have been shown to influence cancer's hallmarks. Recent research has shown miRNA's potential as a therapeutic target and biomarker. In this review, we discussed the synthesis and regulation of miRNA, as well as its dysregulation in human cancer and other disorders, as well as some of the therapeutic applications of miRNA.

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GDF15 expression in metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.116 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 116-116

Author(s):

Priya Jayachandran ◽

Joanne Xiu ◽

Shivani Soni ◽

Richard M. Goldberg ◽

Benjamin Adam Weinberg ◽

...

Keyword(s):

Colon Cancer ◽

T Cells ◽

Nk Cells ◽

Chromatin Remodeling ◽

Cancer Progression ◽

Cd8 T Cells ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Metastatic Colon Cancer ◽

Genomic Alterations

116 Background: Cachexia affects many cancer patients. Growth differentiation factor-15 (GDF15) is a protein that regulates weight and the stress response of cells. The GDF15 gene encodes a ligand of TGF-beta that triggers cachexia and modulates the progression from tumorigenesis to metastasis. Inhibition of GDF15 with an antibody restored muscle mass and fat in animal models. Serum levels rise in proportion to the progression of colon cancer, predict outcome, and have been correlated with CEA. Methods: We retrospectively reviewed 7607 CRC tumors profiled by Caris Life Sciences (Phoenix, AZ) from 2019 to 2020. Profiling included whole transcriptome sequencing (RNA-Seq by NovoSeq). Tumor mutational burden, mismatch repair status, and pathway genomic alterations were evaluated. QuantiSEQ was used to assess immune cell infiltration in the tumor microenvironment. Results: GDF15 expression ranged from 0 to 593 transcripts per million (TPM) with median of 30 (IQR = 15.02). There was no association with age, sex, or primary tumor sidedness. MSI-H/dMMR tumors had higher GDF15 expression (median 37 vs 30, p = 0.0004); TMB > = 17 tumors was seen in 5.9% of bottom quartile (Q1) GDF15 expressors and 8.3% of top quartile (Q4). PDL1 IHC positivity was inversely correlated with GDF15 expression (7.1% in Q1 vs. 2.6% in Q4, p < 0.0001). Genomic alterations associated with higher GDF15 expression (Q4 vs Q1) included genes on TGF-B (SMAD2/4), PI3K (PIK3CA, MTOR), chromatin remodeling (ARID1A, KMT2C), DDR (ATM) and Wnt pathway (APC); those inversely associated included MYC CNA and TP53. Q1 tumors had higher CNA of ERBB2 and FGFR1. Relative neutrophils and NK cells in the TME increased from Q1 to Q4 (p < 0.001). There was a decrease in CD8+ T-cells and Treg cells from Q1 to Q4. Conclusions: GDF15 expression correlates with increased dMMR/MSI-H and TMB, but not with PDL1 expression. Mutations and activated pathways associated with GDF15 expression may explain increased cachexia with more aggressive disease. The association with chromatin remodeling may warrant therapies targeting histone modification and epigenetics. The increase in NK cells but decrease in CD8+ T cells in the TME with increasing GDF15 suggests approaches to treatment. Higher CD8+ lymphocyte counts correlate with PFS with immunotherapy. Anti-PD-L1 therapy reinvigorates the killing function of CD8+ T cells. The decrease in CD8+ T cells and PDL1 positivity with rising GDF15 suggests worse outcome and a lack of response to anti-PDL1 therapy. NK cell checkpoint inhibitors, CARs, and an anti-GFRAL antibody are now in clinical trials and might be utilized in high GDF15 cancers. GDF15 is emerging as a target in the treatment of obesity and cachexia and as a prognostic marker in oncology. Understanding its expression in metastatic colon cancer may reveal which patients could benefit from developing anti-GDF15 targeted therapies against cancer progression.

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