Inhibition of the PD-L1/PD-1 signalling pathway in treating cancer
Programmed Death-Ligand 1 (PD-L1) is a tumour inhibitor that works by modulating immune-tumour cellular interactions. This protein has been found to suppress the immune system during particular events such as pregnancy and autoimmune diseases.
New cancer therapeutic approaches are targeting PD-L1 inhibitors and the outcomes have been promising. In fact, inhibition of the PD-L1/PD-1 signalling pathway has proven to be a safe and effective approach to promote durable anti-cancer responses in several solid tumours, also leading to reduced side effects.
However, recent studies showed that robust antitumour responses to these inhibitors are apparent only in small groups of patients. Additionally, several types of cancer can be highly unresponsive to tumour inhibitor treatments. For this reason, it is pivotal to determine what are the factors that induce either a response or resistance to treatment in order to further develop and improve existing therapies.
Blocking TGFβ could help cancer therapy
Findings from a new study, recently published in Nature, showed that blocking Transforming Growth Factor Beta (TGFβ) could help treatment of those cancers that showed to be resistant to inhibitor therapies.
Researchers examined a large group of patients affected by metastatic urothelial cancer who were treated with an anti-PD-L1 agent (Atezolizumab). The aim was to observe the response to the inhibitor and evaluate treatment for a specific type of cancer. Atezolizumab is an engineered monoclonal antibody targeting the PD-L1 cascade. It is used to treat locally both advanced or metastatic urothelial cancer and non-small cell lung cancer.
During the experiment, response to treatment was associated with CD8+ T-effector cell phenotype. On the other hand, unresponsiveness was linked to a signature of TGFβ signalling in fibroblasts. Patients which showed to be unresponsive to the treatment also showed exclusion of CD8+ T cells from the tumour parenchyma: these cells were instead found in the peritumoural stroma.
New avenues for therapy
TGFβ resulted to play a role in shaping the tumour microenvironment in a way to limit anti-tumour immunity by limiting T-cell infiltration. Furthermore, this study suggests that combining TGFβ-blocking antibodies with an anti-PD-L1 therapy would result in decreasing tumour growth in comparison to either treatment alone.
Other tumour types beyond metastatic urothelial cancer could be observed under this new light. On this front, recent works have aimed to characterise PD-L1 and immune gene expression during breast cancer progression. These results certainly open new avenues for cancer immunotherapy research even if research in this field is still at an early stage.
From this paper, Fios have made an example report to show our bespoke reporting methods. Email us today for access to the report.
Click below to access the paper:
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
Authors: Sanjeev Mariathasan, Shannon J. Turley, Dorothee Nickles, Alessandra Castiglioni, Kobe Yuen, Yulei Wang, Edward E. Kadel III, Hartmut Koeppen, Jillian L. Astarita, Rafael Cubas, Suchit Jhunjhunwala, Romain Banchereau, Yagai Yang, Yinghui Guan, Cecile Chalouni, James Ziai, Yasin Şenbabaoğlu, Stephen Santoro, Daniel Sheinson, Jeffrey Hung, Jennifer M. Giltnane, Andrew A. Pierce, Kathryn Mesh, Steve Lianoglou, Johannes Riegler, Richard A. D. Carano (Genentech), Pontus Eriksson, Mattias Höglund (Lund University), Loan Somarriba, Daniel L. Halligan (Fios Genomics)
