IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3+ CD8+ T Cells to Drive Squamous Cell Carcinoma Regression

Abstract

Ultraviolet (UV) radiation-induced tumours carry a high mutational load, are highly immunogenic, and often fail to grow when transplanted into normal, syngeneic mice. The aim of this study was to investigate factors critical for the immune-mediated rejection of cutaneous squamous cell carcinoma (SCC). In our rejection model, transplanted SCC establish and grow in mice immunosuppressed with tacrolimus. When tacrolimus is withdrawn, established SCC tumours subsequently undergo immune-mediated tumour rejection. Through the depletion of individual immune subsets at the time of tacrolimus withdrawal, we established a critical role for CD8+ T cells, but not CD4+ T cells, γδ T cells, or NK cells, in driving the regression of SCC. Regression was critically dependent on IFN-γ, although IFN-γ was not directly cytotoxic to SCC cells. IFN-γ-neutralisation abrogated SCC regression, significantly reduced CD8+ T cell-infiltration into SCC, and significantly impaired the secretion of CXCL9, CXCL10 and CCL5 within the tumour microenvironment. A strong positive correlation was revealed between CXCL10 expression and CD8+ T cell abundance in tumours. Indeed, blockade of the CXCL10 receptor CXCR3 at the time of tacrolimus withdrawal prevented CD8+ T cell infiltration and the regression of SCC. Chimeric models revealed an important role for immune cells as producers of IFN-γ, but not as recipients of IFN-γ signals via the IFN-γ receptor. Together, these findings suggest a key role for IFN-γ in driving the expression of chemokines within the tumour environment essential for the destruction of established SCC by CD8+ T cells.

Cutaneous Squamous Cell Carcinoma Arising in Immunosuppressed Patients: A Systematic Review of Tumor Profiling Studies

“…No difference between groups in percentage of cells with Mcl-1 expression ( P = 1.00), Bcl-xL expression intensity ( P = 0.134), or the percentage of cells with Bcl-xL expression ( P = 1.00). Tacrolimus Zeng et al. 2021 Mice treated with tacrolimus IFN-γ–neutralization abrogated SCC regression, significantly reduced CD8+ T-cell infiltration into SCC, and significantly impaired the secretion of CXCL9, CXCL10, and CCL5 within the tumor microenvironment.…”

“…(2015) revealed increased signaling of Nfatc1 in CsA-treated mice, with associated increased spontaneous SCC formation ( Goldstein et al., 2015 ). Other murine studies found that tacrolimus-treated mice showed higher numbers of chromosomal aberrations than CsA, sirolimus, and mycophenolate ( Dworkin et al., 2009 ), and that IFN-γ–neutralization in tacrolimus-treated mice abrogated SCC regression, significantly reducing CD8+ T-cell infiltration into SCC, and significantly impairing the secretion of CXCL9, CXCL10, and CCL5 within the tumor microenvironment ( Zeng et al., 2021 ). Other notable findings included reduced expression intensity of Mcl-1 in tacrolimus-treated RTRs compared with sirolimus-treated RTRs and ICPs ( Burke et al., 2015 ), augmented tumor growth in CsA-treated human cells lines through activation of TGFβ-activated kinase 1 (TAK1) ( Xu et al., 2011 ), and greater abundance of MMP-26 expression in cancer cells ( P = 0.04), and MMP-9 in neutrophils ( P = 0.005) in SCCs of patients taking CsA ( Table 4 ) ( Kuivanen et al., 2009 ).…”

Distinct sets of molecular characteristics define tumor-rejecting neoantigens

“…Consistent with our findings, studies in other cSCC models found a dominant role of CD8 T cells and either no role or a supporting role for CD4 T cells. 40, 41, 42, 43 In other tumor models, CD4 T cells and MHC class II neoantigens are required for optimal responses to neoantigen-based immunotherapy or response to immune checkpoint inhibitors. 12, 14 A key difference in these models is that CD4 T cells contribute significantly to the anti-tumor immune responses, as depletion of CD4 T cells alone dramatically increases tumor growth.…”

Natural killer cells suppress human cutaneous squamous cell carcinoma cancer cell survival and tumor growth

“…Thus, it is not surprising that CSCC tumors also respond to a range of immune therapies 7 . NK cells can directly interact with CSCC tumor cells 38 and CLEC2A‐positive fibroblasts to suppress tumor growth 39 . In addition, NK cells and Langerhans cells cooperate to suppress 1,12‐dimethylbenz(a)anthracene including tumor CSCC growth in mice 40 .…”