Understanding the Squamous Cell Carcinoma Immune Microenvironment

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2023 Feb 16

PMID 36793738

Authors

Vahide Saeidi

Nicole Doudican

John A Carucci

Affiliations

Soon will be listed here.

Abstract

Primary cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with a rising incidence of about 1.8 million in the United States annually. Primary cSCC is usually curable by surgery; however, in some cases, cSCC eventuates in nodal metastasis and death from disease specific death. cSCC results in up to 15,000 deaths each year in the United States. Until recently, non-surgical options for treatment of locally advanced or metastatic cSCC were largely ineffective. With the advent of checkpoint inhibitor immunotherapy, including cemiplimab and pembrolizumab, response rates climbed to 50%, representing a vast improvement over chemotherapeutic agents used previously. Herein, we discuss the phenotype and function of SCC associated Langerhans cells, dendritic cells, macrophages, myeloid derived suppressor cells and T cells as well as SCC-associated lymphatics and blood vessels. Possible role(s) of SCC-associated cytokines in progression and invasion are reviewed. We also discuss the SCC immune microenvironment in the context of currently available and pipeline therapeutics.

Citing Articles

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References

Chang D, Shain A . The landscape of driver mutations in cutaneous squamous cell carcinoma. NPJ Genom Med. 2021; 6(1):61. PMC: 8285521. DOI: 10.1038/s41525-021-00226-4. View

Nestle F, Burg G, Fah J, Nickoloff B . Human sunlight-induced basal-cell-carcinoma-associated dendritic cells are deficient in T cell co-stimulatory molecules and are impaired as antigen-presenting cells. Am J Pathol. 1997; 150(2):641-51. PMC: 1858265. View

Li Y, Hanna G, Laga A, Haddad R, Lorch J, Hammerman P . Genomic analysis of metastatic cutaneous squamous cell carcinoma. Clin Cancer Res. 2015; 21(6):1447-56. PMC: 4359951. DOI: 10.1158/1078-0432.CCR-14-1773. View

Tel J, Schreibelt G, Sittig S, Mathan T, Buschow S, Cruz L . Human plasmacytoid dendritic cells efficiently cross-present exogenous Ags to CD8+ T cells despite lower Ag uptake than myeloid dendritic cell subsets. Blood. 2012; 121(3):459-67. DOI: 10.1182/blood-2012-06-435644. View

Ko Y, Chien H, Jiang-Shieh Y, Chang C, Pai M, Huang J . Endothelial CD200 is heterogeneously distributed, regulated and involved in immune cell-endothelium interactions. J Anat. 2009; 214(1):183-95. PMC: 2667927. DOI: 10.1111/j.1469-7580.2008.00986.x. View

Moussai D, Mitsui H, Pettersen J, Pierson K, Shah K, Suarez-Farinas M . The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C. J Invest Dermatol. 2010; 131(1):229-36. DOI: 10.1038/jid.2010.266. View

Yu P, Fu Y . Tumor-infiltrating T lymphocytes: friends or foes?. Lab Invest. 2006; 86(3):231-45. DOI: 10.1038/labinvest.3700389. View

Rowe D, Carroll R, Day Jr C . Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992; 26(6):976-90. DOI: 10.1016/0190-9622(92)70144-5. View

Edwards J, Zhang X, Frauwirth K, Mosser D . Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol. 2006; 80(6):1298-307. PMC: 2642590. DOI: 10.1189/jlb.0406249. View

10.

Zhang S, Cherwinski H, Sedgwick J, Phillips J . Molecular mechanisms of CD200 inhibition of mast cell activation. J Immunol. 2004; 173(11):6786-93. DOI: 10.4049/jimmunol.173.11.6786. View

11.

Steinbrink K, Jonuleit H, Muller G, Schuler G, Knop J, Enk A . Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood. 1999; 93(5):1634-42. View

12.

Wu F, Weigel K, Zhou H, Wang X . Paradoxical roles of TGF-β signaling in suppressing and promoting squamous cell carcinoma. Acta Biochim Biophys Sin (Shanghai). 2017; 50(1):98-105. PMC: 5846704. DOI: 10.1093/abbs/gmx127. View

13.

Ii M, Yamamoto H, Adachi Y, Maruyama Y, Shinomura Y . Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Exp Biol Med (Maywood). 2005; 231(1):20-7. DOI: 10.1177/153537020623100103. View

14.

Trinchieri G . Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003; 3(2):133-46. DOI: 10.1038/nri1001. View

15.

Curd L, Favors S, Gregg R . Pro-tumour activity of interleukin-22 in HPAFII human pancreatic cancer cells. Clin Exp Immunol. 2012; 168(2):192-9. PMC: 3390520. DOI: 10.1111/j.1365-2249.2012.04570.x. View

16.

Neinaa Y, Ahmad El-Ashmawy A, Alshenawy H, Dorgham W . The Prognostic Value of Podoplanin Expression in Nonmelanoma Skin Cancers: Correlation With Lymphatic Vessel Density. Am J Dermatopathol. 2019; 42(6):432-438. DOI: 10.1097/DAD.0000000000001561. View

17.

Mueller M, Peter W, Mappes M, Huelsen A, STEINBAUER H, Boukamp P . Tumor progression of skin carcinoma cells in vivo promoted by clonal selection, mutagenesis, and autocrine growth regulation by granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Am J Pathol. 2001; 159(4):1567-79. PMC: 1850484. DOI: 10.1016/S0002-9440(10)62541-2. View

18.

Kosmidis M, Dziunycz P, Suarez-Farinas M, Muhleisen B, Scharer L, Lauchli S . Immunosuppression affects CD4+ mRNA expression and induces Th2 dominance in the microenvironment of cutaneous squamous cell carcinoma in organ transplant recipients. J Immunother. 2010; 33(5):538-46. DOI: 10.1097/CJI.0b013e3181cc2615. View

19.

Di Nardo L, Pellegrini C, Di Stefani A, Del Regno L, Sollena P, Piccerillo A . Molecular genetics of cutaneous squamous cell carcinoma: perspective for treatment strategies. J Eur Acad Dermatol Venereol. 2019; 34(5):932-941. DOI: 10.1111/jdv.16098. View

20.

Pinzon-Charry A, Maxwell T, Lopez J . Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol. 2005; 83(5):451-61. DOI: 10.1111/j.1440-1711.2005.01371.x. View