TY - JOUR
T1 - Early antitumor activity of oral Langerhans cells is compromised by a carcinogen
AU - Saba, Yasmin
AU - Aizenbud, Itay
AU - Matanes, Daniela
AU - Koren, Noam
AU - Barel, Or
AU - Zubeidat, Khalid
AU - Capucha, Tal
AU - David, Eyal
AU - Eli-Berchoer, Luba
AU - Stoitzner, Patrizia
AU - Wilensky, Asaf
AU - Amit, Ido
AU - Czerninski, Rakefet
AU - Yona, Simon
AU - Hovav, Avi Hai
N1 - Funding Information: ACKNOWLEDGMENTS. This work was supported by the Israel Cancer Research Fund (Project Grant 2020 to A.-H.H.). The S.Y. laboratory is supported by the Israel Science Foundation (Awards 316/20 and 192/20). Funding Information: An early protective role was demonstrated for epidermal LCs during carcinogen-induced skin SCC, in which production of TNF-? by LCs induces the expression of CCL2 and CXCL10 in keratinocytes, resulting in rapid recruitment of NK cells (9). Such a mechanism was not observed here, likely due to the capacity of the carcinogen to down-regulate TNF-? signaling in oral epithelial cells. It is worth mentioning that, in humans, no differences were found in the frequencies of NK cells between healthy and OSCC patients, supporting the limited impact of these cells in oral malignancy (50). Besides the LC-NK cell axis, ??T cells were also reported to inhibit carcinogen-induced skin SCC via their capacity to express NKG2D, enabling elimination of keratinocytes expressing stress ligands (51, 52). While stress ligands were also up-regulated in our system, oral ??T cells do not express NKG2D and are dispensable for the early elimination of damaged ?H2AX+ cells. This might be attributed, in part, to the distinct subsets of ??T cells residing in each epithelium. The epidermis is composed of V?5+ T cells, which are recognized to have cytotoxic activity, while the tongue epithelium is populated by the IL -17-producing V?6+ T cells that have been reported to exhibit both anti- and protumor capabilities (53). Taken together, NK and ??T cells are dispensable during the initiation of oral carcinogenesis, underlining the importance of LC-induced ??T cells in eliminating transformed cells This work was supported by the Israel Cancer Research Fund (Project Grant 2020 to A.-H.H.). The S.Y. laboratory is supported by the Israel Science Foundation (Awards 316/20 and 192/20). Publisher Copyright: © This article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
PY - 2022/1/18
Y1 - 2022/1/18
N2 - Early diagnosis of oral squamous cell carcinoma (OSCC) remains an unmet clinical need. Therefore, elucidating the initial events of OSCC preceding tumor development could benefit OSCC prognosis. Here, we define the Langerhans cells (LCs) of the tongue and demonstrate that LCs protect the epithelium from carcinogen-induced OSCC by rapidly priming αβT cells capable of eliminating γH2AX+ epithelial cells, whereas γδT and natural killer cells are dispensable. The carcinogen, however, dysregulates the epithelial resident mononuclear phagocytes, reducing LC frequencies, while dendritic cells (DCs), macrophages, and plasmacytoid DCs (pDCs) populate the epithelium. Single-cell RNA-sequencing analysis indicates that these newly differentiated cells display an immunosuppressive phenotype accompanied by an expansion of T regulatory (Treg) cells. Accumulation of the Treg cells was regulated, in part, by pDCs and precedes the formation of visible tumors. This suggests LCs play an early protective role during OSCC, yet the capacity of the carcinogen to dysregulate the differentiation of mononuclear phagocytes facilitates oral carcinogenesis.
AB - Early diagnosis of oral squamous cell carcinoma (OSCC) remains an unmet clinical need. Therefore, elucidating the initial events of OSCC preceding tumor development could benefit OSCC prognosis. Here, we define the Langerhans cells (LCs) of the tongue and demonstrate that LCs protect the epithelium from carcinogen-induced OSCC by rapidly priming αβT cells capable of eliminating γH2AX+ epithelial cells, whereas γδT and natural killer cells are dispensable. The carcinogen, however, dysregulates the epithelial resident mononuclear phagocytes, reducing LC frequencies, while dendritic cells (DCs), macrophages, and plasmacytoid DCs (pDCs) populate the epithelium. Single-cell RNA-sequencing analysis indicates that these newly differentiated cells display an immunosuppressive phenotype accompanied by an expansion of T regulatory (Treg) cells. Accumulation of the Treg cells was regulated, in part, by pDCs and precedes the formation of visible tumors. This suggests LCs play an early protective role during OSCC, yet the capacity of the carcinogen to dysregulate the differentiation of mononuclear phagocytes facilitates oral carcinogenesis.
KW - 4NQO
KW - Langerhans cells
KW - Oral cancer
UR - http://www.scopus.com/inward/record.url?scp=85123103511&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.2118424119
DO - https://doi.org/10.1073/pnas.2118424119
M3 - Article
C2 - 35012988
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 3
M1 - e2118424119
ER -
