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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 was observed between indications, in particular within the PD-L1+ tumors. mUC and NSCLC were 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 was 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 revealed molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001006630 1651
EGAD00001006631 Illumina HiSeq 4000 817
EGAD00001006632 Illumina HiSeq 4000 834
EGAD00001006741 817
EGAD00001007585 1651
Publications Citations
Molecular determinants of response to PD-L1 blockade across tumor types.
Nat Commun 12: 2021 3969
A lepidic gene signature predicts patient prognosis and sensitivity to immunotherapy in lung adenocarcinoma.
Genome Med 14: 2022 5
Collaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer.
Nat Commun 13: 2022 6658
Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1<sup>+</sup> T lymphocyte niches through a feed-forward loop.
Cancer Cell 40: 2022 1600-1618.e10
Machine learning-based risk model incorporating tumor immune and stromal contexture predicts cancer prognosis and immunotherapy efficacy.
iScience 26: 2023 107058
Deciphering transcriptomic determinants of the divergent link between PD-L1 and immunotherapy efficacy.
NPJ Precis Oncol 7: 2023 87
Tumour-retained activated CCR7<sup>+</sup> dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity.
Nat Commun 15: 2024 682
Independent prognostic value of CLDN6 in bladder cancer based on M2 macrophages related signature.
iScience 27: 2024 109138
Gene features of tumor-specific T cells relevant to immunotherapy, targeted therapy and chemotherapy in lung cancer.
Heliyon 10: 2024 e28374