Document resource
Background Tumor associated antigens (TAAs) have been studied as primary vaccine targets for more than two decades. However, vaccine trials against TAAs in unselected melanoma patients are largely disappointing. Recently, immune checkpoint blockade (ICB) emerged as an effective therapy for a subset of cancer patients, leading to durable responses. However, few generalizable associations between TAAs and ICB benefit have been reported, although most studies focus on melanoma with highest tumor mutation burden (TMB) among all cancers.Methods In this study, we developed a TAA burden (TAB) algorithm based on known and putative TAAs. Analysis of two ICB clinical studies of urothelial carcinoma revealed that high TMB diminishes association of TAB with ICB benefit.Results Fascinatingly, in TMB-low tumors, TAB shows increased correlation with ICB benefit with decreased CD8 T cell exhaustion signature. This suggests that extensive T cell exhaustion may deplete the TAA-reactive T cell repertoire, thus diminish the association of TAB with ICB benefit. Similar observations are made in two ICB clinical trials for head and neck carcinoma, where TAB shows strong predictive in tumors with unelevated T cell exhaustion signature.Conclusions This study challenges the current paradigm on the lack of association of tumor associated antigen with ICB response and call for future studies on immunogenicity of TAAs and potential TAA-targeted vaccine strategies in TMB low tumors that lack T cell exhaustion signature.