TROP2 is associated with primary resistance to immune checkpoint inhibition in patients with advanced non-small cell lung cancer.

Mechanisms of primary resistance to inhibitors of the programmed cell death-1 (PD-1/PD-L1) signaling axis in non-small cell lung cancer (NSCLC) are still poorly understood. While some studies suggest TROP2's involvement in modulating tumor cell resistance to therapeutic drugs, its specific role in the context of PD1/PD-L1 axis blockade is not definitively established. 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. 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. 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 NSCLC patients who are more likely to benefit from a combination of immunotherapy and an anti-TROP2 agent.