Circulating tumor-associated antigen-specific IFNγ + 4-1BB + CD8 + T cells as peripheral biomarkers of treatment outcomes in patients with pancreatic cancer

CD8 T cells affect the outcomes of pancreatic ductal adenocarcinoma (PDAC). Using tissue samples at pre-treatment to monitor the immune response is challenging, while blood samples are beneficial in overcoming this limitation. In this study, we measured peripheral antigen-specific CD8 T cell responses against four different tumor-associated antigens (TAAs) in PDAC using flow cytometry and investigated their relationships with clinical features. We analyzed the optimal timing within the treatment course for effective immune checkpoint inhibition . We demonstrated that the frequency of TAA-specific IFNγ 4-1BB CD8 T cells was correlated with a fold reduction in CA19-9 before and after neoadjuvant therapy. Moreover, patients with TAA-specific IFNγ 4-1BB CD8 T cells after surgery exhibited a significantly improved disease-free survival. Anti-PD-1 treatment increased the frequency of TAA-specific IFNγ 4-1BB CD8 T cells before neoadjuvant therapy in patients, suggesting the importance of the timing of anti-PD-1 inhibition during the treatment regimen. Our results indicate that peripheral immunophenotyping, combined with highly sensitive identification of TAA-specific responses as well as detailed CD8 T cell subset profiling via analysis, may serve as peripheral biomarkers to predict treatment outcomes and therapeutic efficacy of immunotherapy plus neoadjuvant chemotherapy.