Impaired T cell and neoantigen retention in time serial analysis of lung cancer patients treated with TIL cell therapy

Cell therapy with tumor-infiltrating lymphocytes (TIL) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multi-dimensional analysis was performed on time serial tumor and blood in a lung cancer TIL therapy trial. Using T-cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified neoantigen specific TCRs. We then mapped clones into individual transcriptomes and found that neoantigen-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking neoantigen-reactive clonotypes over time, decay of antigen-reactive peripheral T-cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.