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Defining the Molecular Landscape of Cancer-Associated Stroma in Cutaneous Squamous Cell Carcinoma


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.

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer worldwide. 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 PNI and 9 with PNI) by laser-capture microdissection 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 that 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. However, with PNI, 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.

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer worldwide. 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 PNI and 9 with PNI) by laser-capture microdissection 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 that 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. However, with PNI, 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
05 Vetsuisse Faculty > Veterinärwissenschaftliches Institut > Institute of Veterinary Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Biology
Health Sciences > Dermatology
Life Sciences > Cell Biology
Uncontrolled Keywords:Cell Biology, Dermatology, Molecular Biology, Biochemistry
Language:English
Date:1 December 2022
Deposited On:14 Dec 2022 11:19
Last Modified:28 Jun 2024 01:36
Publisher:Elsevier
ISSN:0022-202X
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jid.2022.06.017
PubMed ID:35850206