*Necessary notice: bioRxiv publishes preliminary scientific reports that aren’t peer-reviewed and, subsequently, shouldn’t be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.
Cancer immunotherapy using immune checkpoint blockade (ICB) agents have proven to be revolutionary in lots of areas of oncology. One option to improve the specificity of this therapy is the usage of molecules that enhance the processing of the tumor cell recognition molecules called class I major histocompatibility antigens 1 (MHC-I), which might be presented to immune cells to activate a cytotoxic response to the tumor.
Study: YAP-controlled MHC I and CXCL10 expression potentiates antitumor immunity independently of IFNγ signaling. Image Credit: Lightspring/Shutterstock
Research shows that the Hippo pathway inside tumor cells is linked to their response to immunotherapy. A recent paper shed some light on how this pathway works via a YAP molecule.
Introduction
ICB showed immense promise that has been only partly fulfilled due to its restricted response in a couple of tumor types and subsets of patients. This has driven intensive research into how tumors reply to ICB depending on their innate mechanisms.
A few of these are known, resembling the activation of and tumor infiltration by cytotoxic CD8 T lymphocytes (CTLs). It is a marker of ICB success. These cells bind to tumor cells following their recognition of the neo-antigens on the tumor cells by the T cell receptor (TCR). This presentation relies on the MHC-I antigen processing and presenting machinery (APM).
This machinery generates antigenic peptides on MHC-I molecules expressed on the cell membranes of all nucleated cells. This important step may be muted in several ways, including mutations within the genome, or by silencing the gene via epigenetic modifications, or at the extent of gene transcription. The result’s a low level of CTL activity against the tumor, allowing it to grow.
Subsequently, the lack of MHC-I expression in several tumor types is linked to poor outcomes.
The MHC-I transactivator (CITA), or NLCR5, is vital to regulating MHC-I APM gene expression at various levels. Altering NLCR5 activity could thus affect the patient’s final result.
Meanwhile, earlier research has shown the crucial regulatory function played by the Hippo pathway in tumor development in mammalian organisms. One in all the components of this pathway is the YAP downstream effector molecule, which is a coactivator in the course of the transcription of varied genes. It must bind to transcriptional aspects resembling TEAD-1-4.
As well as, it is understood that the HIPPO pathway operates inside tumor cells. It regulates antitumor immunity via its effect on B and T cells and macrophages which might be primarily chargeable for recognizing and destroy tumor cells. If this pathway isn’t regulated, the tumor can evade immune surveillance.
The present study, posted on the bioRxiv* preprint server, focused on the role of YAP in regulating MHC-I APM expression inside tumor cells.
What did the study show?
The researchers knocked down the YAP gene in cancer cell lines and used these cells to cause cancers in two sets of mice: one immunodeficient and one immunocompetent. Each showed a discount in tumor growth, by 40% and 60%, respectively. This means that YAP regulates the immune microenvironment and thus affects tumor development.
The scientists found that the inhibition of YAP inside tumor cells led to a rise in NLCR5 and MHC-I APM expression. The NLCR5 and MHC-I APM genes are partially regulated by the Hippo pathway.
The YAP molecule forms a posh with TEAD, to interact directly with one other complex called NuRD. This acts on the promoter region of the NLRC5 gene, stopping its transcription and so reducing the presentation of MHC-1 antigens. This aids immune evasion by the tumor cells, reducing the efficacy of ICB.
Thus, the extent of YAP expression was inversely related to NLCR5 expression and with APM expression. In other words, NLCR5 is a goal gene of YAP/TEAD, and undergoes direct repression when sure by the latter. The final result is the inhibition of MHC-I APM expression via NLCR5.
Concurrently, the chemokine CXCL10, a key component of inflammation, was produced at higher levels. The YAP/TEAD complex perturbs CXCL10 gene expression by binding to the NuRD complex. YAP knockdown led to enhanced CXCL10 expression.
CXCL10 is secreted by tumor cells and attracts CTLs, altering the tumor’s immune microenvironment. The results of YAP inhibition was a big increase in tumor infiltration by CTLs.
Finally, the researchers found that YAP inhibition in mice caused markedly enhanced tumor shrinkage when treated with anti-PD1 antibody, even when the cells were otherwise immune to ICB involving anti-PD1 therapy. This shows that YAP acts to repress antitumor immunity within the host.
What are the implications?
With ICB and other immunotherapies for cancer being significantly limited by immune evasion strategies, there may be an incredible need for newer methods to assist the as much as 90% of patients (depending on the style of tumor) who cannot profit from these treatment approaches. The YAP component of the Hippo pathway is thus a possible novel goal for tumor immunotherapy.
Poor MHC-I antigen processing and presentation are sometimes linked to ICB resistance.
our results suggest that a novel tumor-promoting function of YAP relies on NLRC5 to impair MHC-I antigen processing and presentation and supply a rationale for inhibiting YAP activity in ICB therapy for cancer.”
*Necessary notice: bioRxiv publishes preliminary scientific reports that aren’t peer-reviewed and, subsequently, shouldn’t be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.