Nerve fibers in the Tumor Microenvironment are co-localized with Tertiary Lymphoid Structures

Heij, L. R.; Tan, X.; Kather, J. N.; Niehues, J. M.; Sivakumar, S.; Heussen, N.; van der Kroft, G.; Olde Damink, S. W. M.; Lang, S.; Bednarsch, J.; Aberle, M. R.; Luedde, T.; Gaisa, N.; Liu, D. H. W.; Cleutjens, J. P. M.; Modest, D. P.; Wiltberger, G. J.; Neumann, U. P.

doi:10.1101/2020.08.07.232322

bioRxiv · 10.1101/2020.08.07.232322

Nerve fibers in the Tumor Microenvironment are co-localized with Tertiary Lymphoid Structures

Heij, L. R.·Tan, X.·Kather, J. N.·Niehues, J. M.·Sivakumar, S.·Heussen, N.·van der Kroft, G.·Olde Damink, S. W. M.·Lang, S.·Bednarsch, J.·Aberle, M. R.·Luedde, T.·Gaisa, N.·Liu, D. H. W.·Cleutjens, J. P. M.·Modest, D. P.·Wiltberger, G. J.·Neumann, U. P.

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Abstract

BackgroundB cells and tertiary lymphoid structures (TLS) are reported to be important in the improvement of survival of cancer patients. These secondary lymphoid organs have been associated with the generation of an anti-tumor response. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types and the stromal architecture shapes the intratumoral heterogeneity. The stroma of PDAC is a complex system in which crosstalk takes place between cancer-associated fibroblasts, immune cells, endothelial cells and the cancer cells. Besides immune cells and fibroblasts, there is some limited data about the influence of nerve fibers on cancer progression. Patients and methodsNerve Fiber Density (NFD) was analysed in our cohort of 188 patients with Pancreatic Ductal Adenocarcinoma who underwent pancreatic surgery. We used immunohistochemistry and multiplex imaging to phenotype the immune cell infiltrate. The cell detection classifier measured distance from immune cell to cancer gland and with a heat map we could count TLS. By using Machine learning we were able to define the spatial distribution and counting Tertiary Lymphoid Structures. ResultsHigh NFD is significantly associated with prolonged overall survival (HR 1.676 (95%CI 1.126,2.495) for low vs. high NFD, p-value 0.0109). The immune cells surrounding the nerve fibers were phenotyped in B cells, T cells and dendritic follicular cells, matching a TLS. Here we show that small nerve fibers are located at the TLS in Pancreatic Cancer and a high Nerve Fiber Density combined with more than 5 TLS is associated with a better survival (HR 0.388 (95%CI 0.218, 0.689). ConclusionThe co-localization of small nerve fibers with TLS is a new finding which has not been described before. However the precise roles of these TLS and nerve fibers remains unknown. These findings unravel future pathways and has the potential to reach new directions into already existing targeted therapy.

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Heij, L. R., Tan, X., Kather, J. N., Niehues, J. M., Sivakumar, S., Heussen, N., van der Kroft, G., Olde Damink, S. W. M., Lang, S., Bednarsch, J., Aberle, M. R., Luedde, T., Gaisa, N., Liu, D. H. W., Cleutjens, J. P. M., Modest, D. P., Wiltberger, G. J., Neumann, U. P.. 2020-08-07. Nerve fibers in the Tumor Microenvironment are co-localized with Tertiary Lymphoid Structures. https://doi.org/10.1101/2020.08.07.232322

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