Article ; Online: TROP2 Is Associated with Primary Resistance to Immune Checkpoint Inhibition in Patients with Advanced Non-Small Cell Lung Cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research
2023 Volume 30, Issue 4, Page(s) 779–785
Abstract: Purpose: Mechanisms of primary resistance to inhibitors of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling axis in non-small cell lung cancer (NSCLC) are still poorly understood. While some studies suggest the involvement ... ...
| Abstract | Purpose: Mechanisms of primary resistance to inhibitors of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling axis in non-small cell lung cancer (NSCLC) are still poorly understood. While some studies suggest the involvement of trophoblast cell surface antigen 2 (TROP2) in modulating tumor cell resistance to therapeutic drugs, its specific role in the context of PD-1/PD-L1 axis blockade is not definitively established. Experimental design: We performed high-throughput analysis of transcriptomic data from 891 NSCLC tumors from patients treated with either the PD-L1 inhibitor atezolizumab or chemotherapy in two large randomized clinical trials. To confirm our results at the protein level, we complemented this transcriptional approach by performing a multiplex immunofluorescence analysis of tumor tissue samples as well as a proteomic profiling of plasma. Results: We observed a significant association of TROP2 overexpression with worse progression-free survival and overall survival on PD-L1 blockade, independent of other prognostic factors. Importantly, we found increased TROP2 expression to be predictive of survival in patients treated with atezolizumab but not chemotherapy. TROP2 overexpression was associated with decreased T-cell infiltration. We confirmed these results at the proteomic level both on tumor tissue and in plasma. Conclusions: Our results suggest an important contribution of TROP2 expression to the primary resistance to PD-L1 blockade in NSCLC. TROP2-biomarker-based strategy may be relevant in selecting patients with NSCLC who are more likely to benefit from a combination of immunotherapy and an anti-TROP2 agent. |
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| MeSH term(s) | Humans ; B7-H1 Antigen/metabolism ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Immune Checkpoint Inhibitors/therapeutic use ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Programmed Cell Death 1 Receptor ; Proteomics |
| Chemical Substances | B7-H1 Antigen ; Immune Checkpoint Inhibitors ; Programmed Cell Death 1 Receptor ; TACSTD2 protein, human |
| Language | English |
| Publishing date | 2023-12-04 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1225457-5 |
| ISSN | 1557-3265 ; 1078-0432 |
| ISSN (online) | 1557-3265 |
| ISSN | 1078-0432 |
| DOI | 10.1158/1078-0432.CCR-23-2566 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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