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Immune checkpoints: new targets in kidney cancer

Researchers from SRHI in partnership with the MICS lab (CentraleSupélec, Paris-Saclay University) have identified new immune checkpoints as potential targets in clear cell renal cell carcinoma. The team's results, obtained by pairing statistics and biological analyses, have been published in Cancer Immunology, Immunotherapy.

Published on 22 May 2020

Most adult kidney cancers come in the form of clear cell renal cell carcinoma (ccRCC). This latter is considered immunogenic, that is, the immune system can recognize the tumor and launch a response against it.

Because of that property, the medical community is working particularly on therapies targeting "immune checkpoints", which are ligand-receptor interactions that normally serve to keep the immune system from attacking its host. When the ligand is on a ccRCC cell however, it stops the immune cell from launching an attack on the tumor. Thus, a number of checkpoint inhibitors (e.g., anti-checkpoint antibodies) have been developed and shown effective against ccRCC. Nonetheless, they do not work in numerous patients, suggesting the existence of currently unknown immunosuppressive mechanisms within the tumor or in its microenvironment. It is in this setting that researchers from the Immuno-Hematology Research Department (SRHI), in partnership with the Mathematics and Computer Science Laboratory for Complexity and Systems (MICS; CentraleSupélec, Paris-Saclay University) decided to identify novel checkpoints expressed specifically in ccRCC that may serve as new therapeutic targets.

To achieve their objectives, the team paired, on one hand, advanced statistical methods to analyze the transcriptomics data collected by the Cancer Genome Atlas Program¹, and on the other, immunohistochemical and flow cytometry biological validation protocols. That approach enabled the identification and classification of 44 checkpoints, many of which were previously unknown, expressed in ccRCC samples. The team furthermore used recursive feature elimination to identify HLA-G and PD-L1 as the most pertinent checkpoint proteins. Thus, targeting HLA-G either concurrently with or in case of non-response to anti-PD1/PD-L1 treatments may have potential as a therapeutic strategy.

The results of the SRHI-MICS study underline the importance of expanding the search for treatment targets in ccRCC to guide the development of personalized and more efficacious immunotherapies.

1 : The Cancer Genome Atlas was launched in 2005 to catalog genetic mutations associated with cancer using genome sequencing and bioinformatics. It is a joint project of the American National Cancer Institute (NIH/NCI) and the National Human Genome Research Institute (NIH/NHGRI) and financed by the American government.

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