Identifying TIS as a biomarker for the emergence of ICOS-hi CD4 T cells and calculating a threshold for TISvopra. Various tumor biomarkers were evaluated for their ability to predict the emergence of a peripheral ICOS-hi CD4 T-cell population in response to vopratelimab monotherapy or with nivolumab. A, The 18 TIS genes are associated with antigen presentation, lymphocyte abundance, IFN activity, and T-cell exhaustion, including activation of CD4 T cells. Genes highlighted in blue are involved in antigen presentation to CD4 T cells (HLA-DRB1 and HLA-DQA1) and successful recruitment of T cells and antigen-presenting cells (CCL5 and CXCL9). B, ROC curve demonstrating the ability of TIS to predict ICOS-hi CD4 T-cell emergence (n = 27, AUC = 0.83) and the lack of prediction by PD-L1 IHC (n = 24, AUC = 0.55). AUC, area under the curve; ICOS, inducible costimulator; IHC, immunohistochemistry; PD-L1, programmed death-ligand 1; ROC, receiver operating characteristic; TIS, tumor inflammation signature.