Roche Identifies Biomarker that Determines Patient Response to Immunotherapy

By Rajaneesh K. Gopinath, Ph.D.

A new study conducted by researchers from Roche find that dendritic cells are key targets of immune checkpoint inhibitors and their abundance might determine patient responsiveness to atezolizumab, their PD-L1 blockade immunotherapy agent.

Humans get exposed to plenty of infectious agents frequently, but thanks to our specialized immune system, we are usually capable of thwarting them. However, in autoimmune disease patients, this natural defense mechanism could work against the body by erroneously attacking normal cells. Statistics suggest that, although rare, 4% of the world’s population suffers from approximately 80 autoimmune diseases. In healthy individuals, though, the immune system is well guarded by immune checkpoint proteins such as PD-1 and PD-L1 among others to prevent autoimmunity.

PD-1 is the cell surface receptor present on the T cell. It is bound by the PD-L1 proteins expressed by immune cells like dendritic cells to prevent unnecessary reactions and regulate an immune response only when required. However, in the event of cancer, dendritic cells capture the mutated antigen present on tumors and present it to the T cell (antigen presentation). This will stimulate T cell priming and activation allowing the activated T cells to infiltrate the tumor microenvironment and kill the tumors.

Unfortunately, cancer cells have also evolved to fool the immune system by developing adaptive immune resistance. By overexpressing PD-L1 proteins on their own and binding with PD-1 on the T cells, tumors cleverly evade the immune system by inhibiting T cell activation. This Nobel prize winning discovery led to the rapid progress of cancer immunotherapy and has led to the development of numerous PD-1/PD-L1 blocking monoclonal antibodies. Among them, a notable few have registered significant efficacy against many cancers and have been approved for use in immunotherapies (See Table). However, not all patients are responsive to immunotherapies and a complete understanding of anticancer immunity is still elusive.

New Findings

PD-1/PD-L1 pathway blockade is believed to revive the dysfunctional T cells from the ill effects of the tumor and fight against cancer’s adaptive immune resistance. Therefore, PD-L1 protein expression on tumor cells and immune cells is currently used as a predictive biomarker to assess a patient’s clinical response to immunotherapy. However, recent evidence suggests that PD-L1 expressed by immune cells is a better biomarker. The exact role played by dendritic cells in T cell priming in the event of PD-1/PD-L1 blockade is still unknown.

Researchers from Roche have now found that dendritic cells are key targets of anti-PD-L1 antibodies. Their study published in Science Translational Medicine demonstrates that atezolizumab (Tecentriq) blocks the cis interaction of PD-L1 with CD80 in the tumor-associated dendritic cells. This, in turn, results in the free CD80 to bind with the CD28 receptor on T cells and initiate costimulatory signaling involved in T cell priming.

To confirm their observations, they also analyzed tumor specimens from 59 patients with renal cell carcinoma and 188 patients with non small cell lung cancer (NSCLC) who were under atezolizumab treatment. Their analysis revealed a dendritic cell (DC) gene signature, a gene expression pattern specific to dendritic cells, that correlated with improved overall survival. The high DC signature patients clearly showed a higher overall survival benefit to atezolizumab treatment than their low DC signature counterparts. This difference was not seen when patients were treated with the chemotherapy drug docetaxel suggesting that this observation is specific to checkpoint blockade. Overall, their data suggest that immune checkpoint inhibitors confer anticancer properties to the T cell via reinvigorating the dendritic cell function. The researchers have also filed a patent for an in vitro method that determines the abundance of dendritic cells in a tumor tissue sample. Using this abundance data they intend to predict patient responsiveness to atezolizumab immunotherapy.

Related Article: Janssen Bags FDA Breakthrough Therapy Designation for Lung Cancer Drug

References

1. https://nationalstemcellfoundation.org/glossary/autoimmune-disease/
2. https://stm.sciencemag.org/content/12/534/eaav7431
3. https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=67C8979BAE6D593B2958133F418671DA.wapp2nA?docId=WO2018055145&tab=PCTDESCRIPTION

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Author

Rajaneesh K. Gopinath