Researchers explore potential new target for cancer immunotherapy

By Dr. Liji Thomas, MDReviewed by Aimee MolineuxFeb 27 2023

Cancer immunotherapy using immune checkpoint blockade (ICB) agents have proven to be revolutionary in many areas of oncology. One way to improve the specificity of this therapy is the use of molecules that enhance the processing of the tumor cell recognition molecules called class I major histocompatibility antigens 1 (MHC-I), that are presented to immune cells to activate a cytotoxic response to the tumor.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Research shows that the Hippo pathway within 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 because of its restricted response in a few tumor types and subsets of patients. This has driven intensive research into how tumors respond to ICB depending on their innate mechanisms.

Some of these are known, such as the activation of and tumor infiltration by cytotoxic CD8 T lymphocytes (CTLs). This 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 depends 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 crucial step can be muted in several ways, including mutations in the genome, or by silencing the gene via epigenetic modifications, or at the level of gene transcription. The result is a low level of CTL activity against the tumor, allowing it to grow.

Therefore, the loss of MHC-I expression in several tumor types is linked to poor outcomes.

The MHC-I transactivator (CITA), or NLCR5, is key to regulating MHC-I APM gene expression at various levels. Altering NLCR5 activity could thus affect the patient’s outcome.

Meanwhile, earlier research has shown the crucial regulatory function played by the Hippo pathway in tumor development in mammalian organisms. One of the components of this pathway is the YAP downstream effector molecule, which is a coactivator during the transcription of various genes. It must bind to transcriptional factors such as TEAD-1-4.

In addition, it is known that the HIPPO pathway operates within tumor cells. It regulates antitumor immunity via its effect on B and T cells and macrophages that are primarily responsible for recognizing and destroy tumor cells. If this pathway is not regulated, the tumor can evade immune surveillance.

The current study, posted on the bioRxiv* preprint server, focused on the role of YAP in regulating MHC-I APM expression within 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. Both showed a reduction in tumor growth, by 40% and 60%, respectively. This indicates that YAP regulates the immune microenvironment and thus affects tumor development.

The scientists found that the inhibition of YAP within tumor cells led to an increase 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 complex with TEAD, to interact directly with another complex called NuRD. This acts on the promoter region of the NLRC5 gene, preventing 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 level of YAP expression was inversely associated with NLCR5 expression and with APM expression. In other words, NLCR5 is a target gene of YAP/TEAD, and undergoes direct repression when bound by the latter. The end result is the inhibition of MHC-I APM expression via NLCR5.

Simultaneously, 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 result of YAP inhibition was a significant 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 resistant to ICB involving anti-PD1 therapy. This shows that YAP acts to repress antitumor immunity in the host.

What are the implications?

With ICB and other immunotherapies for cancer being significantly limited by immune evasion strategies, there is a great need for newer methods to help the up to 90% of patients (depending on the type of tumor) who cannot benefit from these treatment approaches. The YAP component of the Hippo pathway is thus a potential novel target for tumor immunotherapy.

Poor MHC-I antigen processing and presentation are often linked to ICB resistance.

our results suggest that a novel tumor-promoting function of YAP depends on NLRC5 to impair MHC-I antigen processing and presentation and provide a rationale for inhibiting YAP activity in ICB therapy for cancer.”

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.