Checkpoint Markers and Tumor Microenvironment: What Do We Know?

Ephraim, Ramya; Fraser, Sarah; Nurgali, Kulmira; Apostolopoulos, Vasso

doi:10.3390/cancers14153788

Cited by 18 publications

(9 citation statements)

References 49 publications

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“…When tumor cells with low immunogenicity multiply, their dormancy in the equilibrium phase is abruptly broken, signaling their entry into the final escape phase. Tumor cells grow by passing various regulatory pathways, apoptosis, and by establishing an immune suppressive TME [21][22][23]. These cells continue to grow and mimic the action of the surrounding cells and become clinically significant by this stage.…”

Section: Immunoeditingmentioning

confidence: 99%

Configuring Therapeutic Aspects of Immune Checkpoints in Lung Cancer

Khadela

Chavda

Postwala

et al. 2023

Cancers

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Immune checkpoints are unique components of the body’s defense mechanism that safeguard the body from immune responses that are potent enough to harm healthy body cells. When proteins present on the surface of T cells recognize and bind to the proteins present on other tumor cells, immune checkpoints are triggered. These proteins are called immunological checkpoints. The T cells receive an on/off signal when the checkpoints interact with companion proteins. This might avert the host’s immune system from eliminating cancer cells. The standard care plan for the treatment of non-small cell lung cancer (NSCLC) has been revolutionized with the use of drugs targeting immune checkpoints, in particular programmed cell death protein 1. These drugs are now extended for their potential to manage SCLC. However, it is acknowledged that these drugs have specific immune related adverse effects. Herein, we discuss the use of immune checkpoint inhibitors in patients with NSCLC and SCLC, their outcomes, and future perspectives.

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Section: Immunoeditingmentioning

confidence: 99%

Configuring Therapeutic Aspects of Immune Checkpoints in Lung Cancer

Khadela

Chavda

Postwala

et al. 2023

Cancers

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“…These include cytotoxic T-lymphocyte-associated antigen (CTLA-4) and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1). The PD-1/PD-L1 pathway is the frontline of interactions between immune cells, stromal cells, and cancer cells [ 121 ].…”

Section: Inflammation and Cancermentioning

confidence: 99%

“…The purpose of cancer immunotherapy is to stimulate cytotoxic T lymphocytes/CD8+ T cells against tumour associated proteins/receptors and, help the initiation of tumour specific T cells in lymphoid organs to achieve efficient and long-lasting anti-tumour immunity [ 125 ]. However, the TME is complicated involving immune cells, cytokines, and checkpoint markers [ 121 ]. Using ICIs as a single agent or in combination treatments with chemotherapy, radiotherapy, or immunotherapeutic intervention, have produced efficient and long-term clinical outcomes [ 19 ].…”

Section: Checkpoint Markersmentioning

confidence: 99%

“… The cancer microenvironment is complex involving diverse immune cells and checkpoint markers. Figure reproduced from Ephraim et al [ 121 ]. CD, cluster of differentiation; CTLA-4, cytotoxic T lymphocyte associated protein 4; DC, dendritic cells; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; LAG3, lymphocyte activation gene 3; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; PDL-1, programmed death ligand 1; PDL-2, programmed death ligand 2; TCR, T cell receptor; TGF, tumour necrosis factor; Tim-3, T cell and immunoglobulin mucin domain 3; Treg, regulatory T cells.…”

Section: Figurementioning

confidence: 99%

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Cancer Immunotherapy: The Checkpoint between Chronic Colitis and Colorectal Cancer

Ephraim

Feehan

Fraser

et al. 2022

Cancers

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Inflammatory Bowel Disease (IBD) is a group of diseases that cause intestinal inflammation and lesions because of an abnormal immune response to host gut microflora. Corticosteroids, anti-inflammatories, and antibiotics are often used to reduce non-specific inflammation and relapse rates; however, such treatments are ineffective over time. Patients with chronic colitis are more susceptible to developing colorectal cancer, especially those with a longer duration of colitis. There is often a limit in using chemotherapy due to side effects, leading to reduced efficacy, leaving an urgent need to improve treatments and identify new therapeutic targets. Cancer immunotherapy has made significant advances in recent years and is mainly categorized as cancer vaccines, adoptive cellular immunotherapy, or immune checkpoint blockade therapies. Checkpoint markers are expressed on cancer cells to evade the immune system, and as a result checkpoint inhibitors have transformed cancer treatment in the last 5–10 years. Immune checkpoint inhibitors have produced long-lasting clinical responses in both single and combination therapies. Winnie mice are a viable model of spontaneous chronic colitis with immune responses like human IBD. Determining the expression levels of checkpoint markers in tissues from these mice will provide insights into disease initiation, progression, and cancer. Such information will lead to identification of novel checkpoint markers and the development of treatments with or without immune checkpoint inhibitors or vaccines to slow or stop disease progression.

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“…RhoA, RhoC, and Rac1 regulate cell cytoskeleton and gene transcription [ 10 , 11 ] and are known to enhance melanoma migration, metastasis, and drug resistance. Enhanced activity of Rho GTPases may contribute to up to 50% of melanoma drug resistance [ 12 , 13 , 14 ]. The effects of Rho depend on gene transcription mechanisms involving serum response transcription factor (SRF) [ 11 , 15 ] and/or YAP/TAZ [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Role of Rho/MRTF in Aggressive Vemurafenib-Resistant Murine Melanomas and Immune Checkpoint Upregulation

Foda,

Neubig

2023

IJMS

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Cutaneous melanoma is the deadliest skin cancer. Most have Ras-MAPK pathway (BRAFV600E or NRAS) mutations and highly effective targeted therapies exist; however, they and immune therapies are limited by resistance, in part driven by small GTPase (Rho and Rac) activation. To facilitate preclinical studies of combination therapies to provide durable responses, we describe the first mouse melanoma lines resistant to BRAF inhibitors. Treatment of mouse lines, YUMM1.7 and YUMMER, with vemurafenib (Vem), the BRAFV600E-selective inhibitor, resulted in high-level resistance (IC50 shifts 20–30-fold). Resistant cells showed enhanced activation of Rho and the downstream transcriptional coactivator, myocardin-related transcription factor (MRTF). Resistant cells exhibited increased stress fibers, nuclear translocation of MRTF-A, and an increased MRTF-A gene signature. Pharmacological inhibition of the Rho/MRTF pathway using CCG-257081 reduced viability of resistant lines and enhanced sensitivity to Vem. Remarkably, co-treatment of parental lines with Vem and CCG-257081 eliminated resistant colony development. Resistant cells grew more slowly in vitro, but they developed highly aggressive tumors with a shortened survival of tumor-bearing mice. Increased expression of immune checkpoint inhibitor proteins (ICIs) in resistant lines may contribute to aggressive in vivo behavior. Here, we introduce the first drug-resistant mouse melanoma models for assessing combinations of targeted and immune therapies.

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Checkpoint Markers and Tumor Microenvironment: What Do We Know?

Cited by 18 publications

References 49 publications

Configuring Therapeutic Aspects of Immune Checkpoints in Lung Cancer

Configuring Therapeutic Aspects of Immune Checkpoints in Lung Cancer

Cancer Immunotherapy: The Checkpoint between Chronic Colitis and Colorectal Cancer

Role of Rho/MRTF in Aggressive Vemurafenib-Resistant Murine Melanomas and Immune Checkpoint Upregulation

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