DOI: 10.1158/1078-0432.ccr-23-1061 ISSN: 1078-0432

A dysfunctional T cell gene signature for predicting non-response to PD-1 blockade in non-small cell lung cancer that is suitable for routine clinical diagnostics

Karlijn Hummelink, Renaud Tissier, Linda J.W. Bosch, Oscar Krijgsman, Michel M. Van den Heuvel, Willemijn S.M.E. Theelen, Diane Damotte, Francois Goldwasser, Karen Leroy, Egbert F. Smit, Gerrit A. Meijer, Daniela S. Thommen, Kim Monkhorst
  • Cancer Research
  • Oncology


Purpose: Since PD-1 blockade is only effective in a minority of patients with advanced stage NSCLC, biomarkers are needed to guide treatment decisions. Tumor infiltration by PD-1T TILs, a dysfunctional tumor-infiltrating lymphocyte (TIL) pool with tumor-reactive capacity, can be detected by digital quantitative IHC and has been established as a novel predictive biomarker in NSCLC. To facilitate translation of this biomarker to the clinic, we here aimed to develop a robust RNA signature reflecting a tumor’s PD-1T TIL status. Experimental Design: mRNA expression analysis using Nanostring was performed in baseline tumor samples from 41 advanced stage NSCLC patients treated with nivolumab that were selected based on PD-1T TIL infiltration by IHC. Samples were included as training cohort (n=41) to develop a predictive gene signature. This signature was independently validated in a second cohort (n=42). Primary outcome was disease control at 12 months (DC 12m) and secondary outcome was progression-free and overall survival. Results: Regularized regression analysis yielded a signature using 12 out of 56 differentially expressed genes between PD-1T IHC high tumors from patients with DC 12m and PD-1T IHC low tumors from patients with progressive disease (PD). In the validation cohort 6/6 (100%) patients with DC 12m and 23/36 (64%) with PD were correctly classified with an NPV of 100% and a PPV of 32%. Conclusions: The PD-1T mRNA signature showed a similar high sensitivity and high NPV as the digital IHC quantification of PD-1T TILs. This provides a straightforward approach allowing for easy implementation in a routine diagnostic clinical setting.

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