Emerging Role of IL-4–Induced Gene 1 as a Prognostic Biomarker Affecting the Local T-Cell Response in Human Cutaneous Melanoma

Abstract

Several studies have emphasized the importance of immune composition of the melanoma microenvironment for clinical outcome. The contribution of IL4I1, a phenylalanine oxidase with immunoregulatory functions, has not been yet explored. Here we studied a primary cutaneous melanoma series from stage I-III patients to investigate the association between in situ IL4I1 expression and clinical parameters or tumor-infiltrating T-cell subsets. IL4I1 was detected in 87% of tumors and was mainly expressed by tumor-associated macrophages and very rare FoxP3 regulatory T cells. The proportion of IL4I1 cells was higher in patients with an ulcerated melanoma or with a positive sentinel lymph node and tended to correlate with a rapid relapse and shorter overall survival. This proportion also correlated positively with the presence of regulatory T cells and negatively with the presence of cytotoxic CD8 T cells. The location of IL4I1 cells may also be relevant to predict prognosis, because their presence near tumor cells was associated with sentinel lymph node invasion and higher melanoma stage. Collectively, our data show that IL4I1 cells shape the T-cell compartment and are associated with a higher risk of poor outcome in melanoma, supporting a key role for IL4I1 in immune evasion.

What role for AHR activation in IL4I1-mediated immunosuppression ?

“…Indeed, the expression of IL4I1 in primary tumors from TCGA correlates very strongly with that of T-cell related genes, as well as others, such as IDO1, which is indicative of the activation of a Th1 and cytotoxic T-cell response in the tumor bed (CD3E = 0.57 ± 0.11, CD8A = 0.49 ± 0.13, IFNG = 0.47 ± 0.13, IDO1 = 0.55 ± 0.15; mean rho ± SD on the six tumor types analyzed; Figure 1(a)). This is in accordance with previous results in human and mouse melanomas 10,12 and with the known regulation of IL4I1 expression by interferons. 4 This is also in line with the reanalysis by Sadik et al of data from Riaz et al, 25 indicating concomitant induction of IL4I1 and IDO1 in patients with advanced melanoma treated with anti-PD-1.…”

“…Thus, a complete understanding of the actions of IL4I1 will be fundamental to facilitating clinical development and avoiding the failure that occurred with epacadostat. 12…”

“…11 In line with this, clinical correlations have been reported between IL4I1 expression by stromal cells and invasion of the sentinel lymph nodes, a higher melanoma stage, and rapid relapse in human primary cutaneous melanomas, in which IL4I1 expression was analyzed by immunohistochemistry. 12 Most interestingly, zones in which IL4I1 expression was concentrated were depleted of cytotoxic CD8 + T cells and enriched with regulatory FoxP3 + T cells. Moreover, IL4I1 was overexpressed in melanoma patients with progressive disease under treatment with the anti-PD-1 antibody nivolumab, suggesting a relation between IL4I1 expression and resistance to immune-checkpoint blockade.…”

The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment

“…Finally, we showed a clinical correlation between IL4I1 expression in primary cutaneous tumors and parameters of poor outcome in patients with melanoma. It was also associated with invasion of the sentinel lymph node, a higher melanoma stage, and rapid relapse and tended to correlate with shorter overall survival, specifically when considering cases in which the IL4I1 + cells were in close contact with tumor cells [37]. IL4I1 has also been suggested to be a significant prognostic parameter in breast cancer, renal cancer, and glioma [38,39] ().…”

IL4I1 Accelerates the Expansion of Effector CD8+ T Cells at the Expense of Memory Precursors by Increasing the Threshold of T-Cell Activation

“…IL4I1 is particularly abundant in the tumor microenvironment of inflammatory human cancers and may be associated with a poor prognosis [reviewed in (4)]. Indeed, murine models have shown that IL4I1 negatively regulates the expansion and functionality of antitumor CD8 + T cells (5,6), an effect that has been confirmed by the analysis of human primary cutaneous melanomas (7).…”