Molecular determinants of response to PD-L1 blockade across tumor types

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. PD-L1 immune checkpoint inhibition has been used for several tumour types. Here, the authors use immunohistochemistry, tumour mutation burden and RNA-seq data from 366 patients with different indications to identify molecular signatures of response to atezolizumab and reveal pathway heterogeneity and the involvement of non-immune pathways.

Automated summary

This study used immunohistochemistry, tumor mutation burden, and RNA-seq data to identify molecular signatures of response to PD-L1 immune checkpoint inhibition across different indications such as NSCLC, UC, and RCC. The results revealed pathway heterogeneity and the involvement of non-immune pathways in the response to checkpoint blockade, highlighting the importance of indication-specific molecular approaches in formulating treatment strategies.