Transcriptional and post-transcriptional regulation of checkpoint genes on the tumour side of the immunological synapse

Abstract

Cancer is a disease of the genome, therefore, its development has a clear Mendelian component, demonstrated by well-studied genes such as BRCA1 and BRCA2 in breast cancer risk. However, it is known that a single genetic variant is not enough for cancer to develop leading to the theory of multistage carcinogenesis. In many cases, it is a sequence of events, acquired somatic mutations, or simply polygenic components with strong epigenetic effects, such as in the case of brain tumours. The expression of many genes is the product of the complex interplay between several factors, including the organism’s genotype (in most cases Mendelian-inherited), genetic instability, epigenetic factors (non-Mendelian-inherited) as well as the immune response of the host, to name just a few. In recent years the importance of the immune system has been elevated, especially in the light of the immune checkpoint genes discovery and the subsequent development of their inhibitors. As the expression of these genes normally suppresses self-immunoreactivity, their expression by tumour cells prevents the elimination of the tumour by the immune system. These discoveries led to the rapid growth of the field of immuno-oncology that offers new possibilities of long-lasting and effective treatment options. Here we discuss the recent advances in the understanding of the key mechanisms controlling the expression of immune checkpoint genes in tumour cells.

Comprehensive Analysis of FASN in Tumor Immune Infiltration and Prognostic Value for Immunotherapy and Promoter DNA Methylation

“…In addition, although Duan et al demonstrated that mir-195-5p is inversely linked with immune cell infiltration in lung adenocarcinoma [ 65 ], the precise molecular mechanism has not been investigated. Dobosz et al showed that miRNAs can also be involved in tumor-cell–immune-cell interactions by regulating post-transcriptional regulation of immune checkpoint genes [ 66 ], which made mir-195-5p development as a small molecule drug more challenging. Taken together, these results demonstrated the tumor therapeutic effect of FASN inhibition by mir-195-5p and future studies may take a new direction into the involvement of mir-195-5p and FASN in the tumor immune response.…”

Acute myeloid leukaemia relapse after allogeneic haematopoietic stem cell transplantation: Mechanistic diversity and therapeutic directions

“…These ICMs are small proteins expressed at the cell surface membrane that need to be either activated or inactivated to trigger immune responses. 48 ICMs suppress the ability of the CD8+ T-cells of the immune system to recognize the malignancy as a target for eradication. These ICM proteins include PD-L1 and PD-L2, both of which are recognized by the PD-1 receptor on T-cells.…”

“…Tumour cells express ICMs to regulate and suppress host response, and facilitate tumour cell survival. These ICMs are small proteins expressed at the cell surface membrane that need to be either activated or inactivated to trigger immune responses 48 . ICMs suppress the ability of the CD8+ T‐cells of the immune system to recognize the malignancy as a target for eradication.…”

“…CD80 and CD86 bind to CTLA‐4 and CD28 receptors on the host T‐cell (Figure 3A,B). 48 The PD‐1 receptor inhibits T‐cell‐mediated recognition of tumour when engaged with PD‐L1 and PD‐L2 on the surface of tumour cells. PD‐L1 expression in the tumour microenvironment induces PD‐1‐mediated exhaustion of T‐cells, resulting in inhibition of the immune system response 49,50 …”

A Prognostic Model for Predicting Liver Cancer Patients Based On Immune Checkpoint Gene-Related Basement Membrane Genes, And Analyzing Immunity and Potential Drug Candidates

“…microenvironment [2][3] . Immune checkpoint gene expression often reduces autoimmune reactivity, and its presence in tumor cells stops the immune system from clearing malignancies 4 . Furthermore, immunological checkpoint genes (ICGs) represent novel targets for cancer therapeutic development 5 .The basement membrane (BM) is the oldest extracellular matrix (ECM) in animals and is made up of several components.…”