Beebe, Erin; Motamed, Zahra; Opitz, Lennart; Cheng, Phil F; Levesque, Mitchell P; Markkanen, Enni; Feldmeyer, Laurence (2022). Defining the molecular landscape of cancer-associated stroma in cutaneous squamous cell carcinoma. Journal of investigative dermatology, 142(12), 3304-3312.e5. Elsevier 10.1016/j.jid.2022.06.017
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1-s2.0-S0022202X22016694-main.pdf - Accepted Version Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND). Download (22MB) | Preview |
Cutaneous squamous cell carcinoma (cSCC) is the 2nd most common skin cancer world-wide. Cancer-associated stroma (CAS) is central to tumor development and strongly influences therapy response. Perineural infiltration (PNI) represents a major risk factor for cSCC and likely influences CAS reprogramming. However, stromal reprogramming in cSCC remains poorly characterized, and it is unknown whether and how PNI influences CAS. To address these questions, we analyzed CAS and matched normal stroma from 20 cSCC cases (11 without and 9 with PNI) by laser-capture microdissection (LCM) using RNA-sequencing. Our analysis reveals extensive stromal reprogramming strongly driven by changes in immune cells, as validated using immunohistochemistry. Furthermore, CAS of cSCC displays markers of immune exhaustion, and multiplex spatial analysis suggests PD-L1 expression on NK-T cells contributes to T cell exhaustion and immunosuppression. Finally, PNI is characterized by increased IL-17A. In PNI negative cases, IL-17A derives predominantly from CD3+ cells. With PNI however, we observe an increased contribution of fibroblasts to high IL-17A, which coincides with a significant increase in FAP+ cells. Our analysis elucidates the molecular landscape of CAS in cSCC and identifies the presence of immunosuppressive mechanisms, supporting further research into immunotherapy and anti-IL-17A in cSCC especially for cases with PNI.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Dermatology |
UniBE Contributor: |
Feldmeyer, Laurence |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
0022-202X |
Publisher: |
Elsevier |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
20 Jul 2022 11:12 |
Last Modified: |
16 Jul 2023 00:25 |
Publisher DOI: |
10.1016/j.jid.2022.06.017 |
PubMed ID: |
35850206 |
Uncontrolled Keywords: |
RNAseq cutaneous squamous cell carcinoma formalin-fixed paraffin embedded laser-capture microdissection tumor microenvironment tumor stroma |
BORIS DOI: |
10.48350/171402 |
URI: |
https://boris.unibe.ch/id/eprint/171402 |
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