Editorial Zheng based immunotherapies are known to activate antigenspecific T-effector cells in the peripheral lympho cytes. However, it is not known whether vaccine-induced adaptive immune response occurs in the TME. We developed a GM-CSF-secreting pancreatic cancer vaccine, which has so far been one of the most widely tested immunotherapies for pancreatic cancer [10–13]. Our prior work demonstrated clinical activity in a subset of vaccinated patients, and showed that the post-vaccination induction of T-cell responses against mesothelin is associated with longer survival [11, 12, 14]. However, up to this point, neither our group nor other groups have had the opportunity to conduct in-depth analyses of the effects of an immune-based therapy on the TME of nonmelanoma solid tumors in patients.

Our group has thus conducted a novel neoadjuvant and adjuvant study designed to evaluate postimmunotherapy changes within the TME of primary pancreatic tumors following treatment with our pancreatic cancer GM-CSF-secreting pancreatic cancer vaccine, given either alone or with immune modulating doses of cyclophosphamide to deplete regulatory T cells [15]. Given with the same pancreatic cancer vaccine, it was previously reported that low dose cyclophosphamide enhanced higher avidity T-cell responses that were associated with longer progression-free survival in patients [11]. Provided opportunities to dissect TME in the wholly resected tumors, the neoadjvuant vaccine study revealed novel findings that would not have been demonstrated in prior studies. Pathological examination of tumor tissue resected just 2 weeks following vaccination identified the formation of immunotherapy-induced tertiary lymphoid aggregates, an organized lymphoid structure that was not observed in tumors resected from unvaccinated patients. Tertiary lymphoid structures have not been previously reported in pancreatic cancer, but have been reported in other cancers at baseline, before therapeutic intervention [16]. Those cancers that demonstrated tertiary lymphoid aggregates at baseline include melanoma and NSCLC, which were also found to respond to the immune checkpoint inhibitors [2–4]. In contrast to primary and secondary lymphoid structure, tertiary lymphoid structures are not pre-existing and are developed only when challenged with antigens [16]. The development of tertiary lymphoid structures is achieved through a lymphoid neogenesis process by