Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Abstract

The present study evaluates the impact of immune cell populations on metastatic development in a model of spontaneous melanoma [mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice)]. In this model, cancer cells disseminate early but remain dormant for several weeks. Then, MT/ ret mice develop cutaneous metastases and, finally, distant metastases. A total of 35% of MT/ret mice develop a vitiligo, a skin depigmentation attributable to the lysis of normal melanocytes, associated with a delay in tumor progression. Here, we find that regulatory CD4 + T cells accumulate in the skin, the spleen, and tumor-draining lymph nodes of MT/ret mice not developing vitiligo. Regulatory T-cell depletion and IL-10 neutralization led to increased occurrence of vitiligo that correlated with a decreased incidence of melanoma metastases. In contrast, inflammatory monocytes/dendritic cells accumulate in the skin of MT/ret mice with active vitiligo. Moreover, they inhibit tumor cell proliferation in vitro through a reactive oxygen species-dependent mechanism, and both their depletion and reactive oxygen species neutralization in vivo increased tumor cell dissemination. Altogether, our data suggest that regulatory CD4 + T cells favor tumor progression, in part, by inhibiting recruitment and/or differentiation of inflammatory monocytes in the skin.T he concept of suppressive T cells, which was first described in the early 1970s, remained poorly investigated until Sakaguchi et al. demonstrated the suppressive functions of a subset of CD4 + T cells now called regulatory T cells (Tregs) (1). Tregs express Foxp3 (2) and high surface levels of the α-chain of the IL-2 receptor (CD25) and are the main mediators of peripheral tolerance under physiological settings (1). Their role in the suppression of antitumor immunity was originally described in the 1980s (3) but remained, at first, largely underestimated. The demonstration that systemic depletion of Tregs favors tumor rejection in mouse models highlighted their contribution in tumor progression (4). Whereas it is established that Tregs potently interfere with tumorspecific T cells (5-8), their impact on innate immune cells, in particular, on myeloid cells, has been clearly less investigated in the context of tumor development (9, 10).To decipher the role of Tregs in the relationship between cancer immunity and autoimmunity, we used mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice) (11). In this model, the primary uveal tumor disseminates early but remains dormant for several weeks (12, 13). MT/ret mice then develop cutaneous metastases and finally distant (i.e., pulmonary, visceral, and mediastinal adenopathy) metastases (14). A significant proportion of MT/ret mice spontaneously develops vitiligo-like depigmentations. The tumor progression is significantly delayed in mice harboring vitiligo compared with mice without depigmented skin (14). The development of vitiligo in melanoma patients has...

Rapid dissemination of RET-transgene-driven melanoma in the presence of non-obese diabetic alleles: Critical roles of Dectin-1 and Nitric-oxide synthase type 2

“…15 Our study revealed a direct correlation between the amplification of this subset within the spleen and the tumor microenvironment and tumor extension (Fig. 2E).…”

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

“…Studies of Smyth line chickens, an animal model for human autoimmune vitiligo, have demonstrated that elevated leukocyte infiltration in early and active vitiligo is accompanied by increased levels of cytokine expression, especially in interferon (IFN)-IL-10, and IL-21 [68]. Recently, in a mouse model of spontaneous melanoma, Treg cell-depletion and IL-10 neutralisation led to an increased occurrence of vitiligo which correlated with a decreased incidence of melanoma metastases [69].…”

One microenvironment does not fit all: heterogeneity beyond cancer cells

“…Clustering of cell surface VCAM-1 triggered Akt activation and protected cancer cells from pro-apoptotic cytokines such as TRAIL. However, anti-metastatic functions of inflammatory monocytes have also been reported [94]. In a mouse model of spontaneous melanoma expressing human RET oncogene, CD11b+ Ly6C high monocytes inhibited tumor cell proliferation through a reactive oxygen species-dependent mechanism.…”