Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer

作者：Andrew J. Gunderson, Venkatesh Rajamanickam, Cynthia Bui, Brady Bernard, Joanna Pucilowska, Carmen Ballesteros‐Merino, Mark Schmidt, Kayla McCarty, Michaela Philips, Brian Piening, Christopher Dubay, Terry R. Medler, Phillipa Newell, Paul Hansen, Eric Tran, Ephraim Tang, Carlo Bifulco, Marka R. Crittenden, Michael J. Gough, Kristina H. Young · 发表于：OncoImmunology · 年份：2021 · DOI：10.1080/2162402x.2021.1900635 · 被引用次数：187 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、T-cell and B-cell Immunology

Pancreatic ductal adenocarcinoma (PDAC) has traditionally been thought of as an immunologically quiescent tumor type presumably because of a relatively low tumor mutational burden (TMB) and poor responses to checkpoint blockade therapy. However, many PDAC tumors exhibit T cell inflamed phenotypes. The presence of tertiary lymphoid structures (TLS) has recently been shown to be predictive of checkpoint blockade response in melanomas and sarcomas, and are prognostic for survival in PDAC. In order to more comprehensively understand tumor immunity in PDAC patients with TLS, we performed RNA-seq, single and multiplex IHC, flow cytometry and predictive genomic analysis on treatment naïve, PDAC surgical specimens. Forty-six percent of tumors contained distinct T and B cell aggregates reflective of “early-stage TLS” (ES-TLS), which correlated with longer overall and progression-free survival. These tumors had greater CD8+ T cell infiltration but were not defined by previously published TLS gene-expression signatures. ES-TLS+ tumors were enriched for IgG1 class-switched memory B cells and memory CD4+ T cells, suggesting durable immunological memory persisted in these patients. We also observed the presence of active germinal centers (mature-TLS) in 31% of tumors with lymphocyte clusters, whose patients had long-term survival (median 56 months). M-TLS-positive tumors had equivalent overall T cell infiltration to ES-TLS, but were enriched for activated CD4+ memory cells, naive B cells a...