MicroRNA-155 Expression Is Enhanced by T-cell Receptor Stimulation Strength and Correlates with Improved Tumor Control in Melanoma

Abstract

microRNAs are short noncoding RNAs that regulate protein expression posttranscriptionally. We previously showed that miR-155 promotes effector CD8 þ T-cell responses. However, little is known about the regulation of miR-155 expression. Here, we report that antigen affinity and dose determine miR-155 expression in CD8 þ T cells. In B16 tumors expressing a low-affinity antigen ligand, tumorspecific infiltrating CD8 þ T cells showed variable miR-155 expression, whereby high miR-155 expression was associated with more cytokine-producing cells and tumor control. Moreover, anti-PD-1 treatment led to both increased miR-155 expression and tumor control by specific CD8 þ T cells. In addition, miR-155 overexpression enhanced exhausted CD8 þ T-cell persistence in the LCMV cl13 chronic viral infection model. In agreement with these observations in mouse models, miR-155 expression in human effector memory CD8 þ T cells positively correlated with their frequencies in tumor-infiltrated lymph nodes of melanoma patients. Low miR-155 target gene signature in tumors was associated with prolonged overall survival in melanoma patients. Altogether, these results raise the possibility that high miR-155 expression in CD8 þ tumorinfiltrating T cells may be a surrogate marker of the relative potency of in situ antigen-specific CD8 þ T-cell responses.

miR-155 Overexpression in OT-1 CD8+ T Cells Improves Anti-Tumor Activity against Low-Affinity Tumor Antigen

“…We and others had previously shown that the upregulation of the endogenous miR-155 is proportional to the affinity of the TCR to the peptide:MHC ligand, both in mouse and human CD8 + T cells. 8,36,45 Together, these observations suggest that overexpressing miR-155 in low-affinity T cells would selectively support their activation and effector functions, as they are the ones with the lowest natural miR-155 increase upon antigen activation. Indeed, we demonstrated that OT-1 cells stimulated with the N4 peptide upregulated miR-155 to a higher level compared to OT-1 cells stimulation with the T4 peptide.…”

“…This hypothesis was indeed supported by our observation that miR-155 is less upregulated in low-affinity T cells. 36 Thus, this observation would suggest that forced miR-155 overexpression may have more impact in a low-affinity T cell response.…”

miRNAs as Key Players in the Management of Cutaneous Melanoma

“…They measured miR-155 expression in CD8 T cells isolated from tumor-infiltrating lymph nodes and tumor tissue samples from melanoma patients and murine models. miR-155 expression in CD8 T cells was found to depend on antigen stimulation [56]. Previous investigations had shown that TCR (T Cell Receptor) is responsible for NF-kB and AP1 activation that in turn, upregulates miR-155 expression [65,66].…”

“…Moreover, the expression of miR-155 is stimulated by IRF4, which is overexpressed in CD8 T cells from Murine lymphocytic choriomeningitis virus chronic infection [55]. Thus, Martinez-Usatorre and colleagues concluded that miR-155 could be considered a marker of responsiveness of CD8 T cells, as further demonstrated by its upregulation after PD1 blockade [56].…”

“…Martinez-Usatorre et al [56] studied the role of miR-155, which had proved to be regulated during CD8 T cells differentiation in previous investigations [64]. They measured miR-155 expression in CD8 T cells isolated from tumor-infiltrating lymph nodes and tumor tissue samples from melanoma patients and murine models.…”