Nerve Fibers in the Tumor Microenvironment Are Co-Localized with Lymphoid Aggregates in Pancreatic Cancer

Lara R Heij; Xiuxiang Tan; Jakob N Kather; Jan M Niehues; Shivan Sivakumar; Nicole Heussen; Gregory van der Kroft; Steven W M Olde Damink; Sven Lang; Merel R Aberle; Tom Luedde; Nadine T Gaisa; Jan Bednarsch; Drolaiz H W Liu; Jack P M Cleutjens; Dominik P Modest; Ulf P Neumann; Georg J Wiltberger

doi:10.3390/jcm10030490

Nerve Fibers in the Tumor Microenvironment Are Co-Localized with Lymphoid Aggregates in Pancreatic Cancer

J Clin Med. 2021 Jan 30;10(3):490. doi: 10.3390/jcm10030490.

Authors

Lara R Heij^{1

2

3}, Xiuxiang Tan^{1

2}, Jakob N Kather⁴, Jan M Niehues⁴, Shivan Sivakumar^{5

6}, Nicole Heussen^{7

8}, Gregory van der Kroft¹, Steven W M Olde Damink^{1

2

9}, Sven Lang¹, Merel R Aberle^{1

2}, Tom Luedde⁴, Nadine T Gaisa³, Jan Bednarsch¹, Drolaiz H W Liu¹⁰, Jack P M Cleutjens^{10

11}, Dominik P Modest¹², Ulf P Neumann^{1

9}, Georg J Wiltberger¹

Affiliations

¹ Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany.
² NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 ER Maastricht, The Netherlands.
³ Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
⁴ Department of Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany.
⁵ Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
⁶ Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK.
⁷ Department of Medical Statistics, RWTH Aachen University, 52074 Aachen, Germany.
⁸ Center of Biostatistics and Epidemiology, Medical School, Sigmund Freud University, 1020 Vienna, Austria.
⁹ Department of Surgery, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands.
¹⁰ Department of Pathology, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands.
¹¹ CARIM Cardiovascular Research Institute Maastricht, Maastricht University, 6229 HX Maastricht, The Netherlands.
¹² Department of Hematology, Oncology and Tumor Immunology, CVK, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.

Abstract

B cells and tertiary lymphoid structures (TLS) are reported to be important in survival in cancer. Pancreatic Cancer (PDAC) is one of the most lethal cancer types, and currently, it is the seventh leading cause of cancer-related death worldwide. A better understanding of tumor biology is pivotal to improve clinical outcome. The desmoplastic stroma is a complex system in which crosstalk takes place between cancer-associated fibroblasts, immune cells and cancer cells. Indirect and direct cellular interactions within the tumor microenvironment (TME) drive key processes such as tumor progression, metastasis formation and treatment resistance. In order to understand the aggressiveness of PDAC and its resistance to therapeutics, the TME needs to be further unraveled. There are some limited data about the influence of nerve fibers on cancer progression. Here we show that small nerve fibers are located at lymphoid aggregates in PDAC. This unravels future pathways and has potential to improve clinical outcome by a rational development of new therapeutic strategies.

Keywords: machine learning; nerve fiber density; pancreatic cancer; spatial arrangements; tertiary lymphoid structures; tumor microenvironment.