Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC).
Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications. Signatures described previously for immune checkpoint inhibitors also failed to validate. At the pathway level, significant heterogeneity is observed between indications, in particular within the PD-L1+ tumors. mUC and NSCLC are molecularly aligned, with cell cycle and DNA damage repair genes associated with response in PD-L1- tumors. At the gene level, the CDK4/6 inhibitor CDKN2A is identified as a significant transcriptional correlate of response, highlighting the association of non-immune pathways to the outcome of checkpoint blockade. This cross-indication analysis reveals molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.
Nature communications. 2021 Jun 25*** epublish ***
Romain Banchereau, Ning Leng, Oliver Zill, Ethan Sokol, Gengbo Liu, Dean Pavlick, Sophia Maund, Li-Fen Liu, Edward Kadel, Nicole Baldwin, Suchit Jhunjhunwala, Dorothee Nickles, Zoe June Assaf, Daniel Bower, Namrata Patil, Mark McCleland, David Shames, Luciana Molinero, Mahrukh Huseni, Shomyseh Sanjabi, Craig Cummings, Ira Mellman, Sanjeev Mariathasan, Priti Hegde, Thomas Powles
Genentech, South San Francisco, CA, USA. ., Genentech, South San Francisco, CA, USA., Foundation Medicine, Cambridge, MA, USA., Baylor Institute for Immunology Research, Dallas, TX, USA., Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, UK. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/34172722