Andrew Gunderson, Assistant Professor at The Ohio State University, shared a post on LinkedIn:
“Online now in Cancer Cell by Cell Press, we provide a molecular explanation for why many pancreatic cancer patients do not form tertiary lymphoid structures/lymphoid aggregates in their tumors. This resistance is largely driven by the predominant subtype of cancer associated fibroblasts observed in human tumors, the wound healing adjacent myofibroblasts (myCAF).
Its clear activating signals from lymphotoxin beta receptor are necessary to form TLS and, in cooperation with TNFR1/2 signaling, push fibroblasts to become fibroblastic reticular cells that secrete CXCL13, CCL19, and CCL21 (we call them rCAF when observed in tumors).
Spatially rCAF reside near TLS in human cancers shown in this study and many others. However, TGF-beta programming into the myCAF state silences rCAF differentiation thereby preventing neogenesis of the lymphocyte-reticular network that proceeds TLS formation. In TLS-resistant PDAC models rich in TGF-beta signaling, when we blocked myCAF differentiation genetically or pharmacologically and then treated with the LTBR agonist, we observed increased T and B cell recruitment and TLS formation.
Tumors in these mice were better controlled and dependent on T cell immunity for the treatment effect. As many groups are interested in therapeutic strategies to induce TLS formation in cancer patients, we hope this guides clinical trial design to consider the counterregulatory factors that might dampen these TLS-activating signals.
Congrats Elijah Kirschstein for his efforts in completing this study, his lab mates Olivia Harder and Madison Sikorski for their critical contributions in animal experiments and imaging, Jordan Krull and Qin Ma for bioinformatics support, Wei Chen for path analysis, Carl Ware for his guidance, reagents, and expertise on LTBR biology, Vaccinex for immunomodulatory antibodies, and Michael Gough and Dr. Kristina Young for cell lines, data and allowing me to initially explore this concept.
Title: Myofibroblast programming blocks differentiation of TLS-organizing fibroblastic reticular cells in pancreatic cancer
Authores: Elijah Kirschstein, Olivia Harder, Jordan Krull, Madison Sikorski, Shrijan Khanal, Morgan Mack, Carl F. Ware, Elizabeth Evans, Michael J. Gough, Qin Ma, Wei Chen, Kristina H. Young, Andrew J. Gunderson.
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