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Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer.
Oncoimmunology
  • Andrew J Gunderson, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon
  • Venkatesh Rajamanickam, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR
  • Cynthia Bui, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, Oregon, United States.
  • Brady Bernard, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, Oregon, United States.
  • Joanna Pucilowska, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR
  • Carmen Ballesteros-Merino, Laboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA.
  • Mark Schmidt, Providence Cancer Institute, Portland, OR
  • Kayla McCarty, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, OR, United States of America
  • Michaela Philips, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, Oregon, United States.
  • Brian D. Piening, Molecular Genomics Laboratory, Providence Portland Medical Center, Portland, OR; Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Cancer Center, Portland, OR.
  • Christopher Dubay, Providence Cancer Center
  • Terry R Medler, Earle A. Chiles Research Institute, Providence Portland Medical Center
  • Phillipa Newell, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, Oregon, United States.
  • Paul D Hansen, Providence Portland Medical Center, Portland, OR.
  • Eric Tran, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, Oregon, United States.
  • Ephraim Tang, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, Oregon, United States.
  • Carlo Bifulco, Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR
  • Marka R Crittenden, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland
  • Michael J Gough, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland
  • Kristina H Young, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, OR, United States of America
Document Type
Article
Publication Date
3-17-2021
Keywords
  • oregon,
  • portland,
  • chiles
Disciplines
Abstract

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 and NK cells. Finally, using a TCGA-PDAC dataset, ES-TLS+ tumors harbored a decreased TMB, but M-TLS with germinal centers expressed significantly more MHCI-restricted neoantigens as determined by an in silico neoantigen prediction method. Interestingly, M-TLS+ tumors also had evidence of increased rates of B cell somatic hypermutation, suggesting that germinal centers form in the presence of high-quality tumor neoantigens leading to increased humoral immunity that confers improved survival for PDAC patients. AbbreviationsTLS: tertiary lymphoid structures; GC: germinal center(s); PDAC: pancreatic ductal adenocarcinoma; RNA-seq: RNA sequencing; BCRseq: B cell receptor sequencing; HEV: high endothelial venule; PNAd: peripheral node addressin; TMB: tumor mutational burden; TCGA: the cancer genome atlas; PAAD: pancreatic adenocarcinoma; FFPE: formalin fixed paraffin embedded; TIME: tumor immune microenvironment.

Clinical Institute
Cancer
Clinical Institute
Digestive Health
Specialty
Earle A. Chiles Research Institute
Specialty
Gastroenterology
Specialty
Oncology
Citation Information
Andrew J Gunderson, Venkatesh Rajamanickam, Cynthia Bui, Brady Bernard, et al.. "Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer." Oncoimmunology (2021)
Available at: http://works.bepress.com/brian-piening/52/