Primary Tr1 cells from metastatic melanoma eliminate tumor-promoting macrophages through granzyme B- and perforin-dependent mechanisms

Abstract

In malignant melanoma, tumor-associated macrophages play multiple roles in promoting tumor growth, such as inducing the transformation of melanocytes under ultraviolet irradiation, increasing angiogenesis in melanomas, and suppressing antitumor immunity. Because granzyme B-and perforin-expressing Tr1 cells could specifically eliminate antigen-presenting cells of myeloid origin, we examined whether Tr1 cells in melanoma could eliminate tumor-promoting macrophages and how the interaction between Tr1 cells and macrophages could affect the growth of melanoma cells. Tr1 cells were characterized by high interleukin 10 secretion and low Foxp3 expression and were enriched in the CD4 + CD49b + LAG-3 + T-cell fraction. Macrophages derived from peripheral blood monocytes in the presence of modified melanoma-conditioned media demonstrated tumor-promoting capacity, exemplified by improving the proliferation of cocultured A375 malignant melanoma cells. But when primary Tr1 cells were present in the macrophage-A375 coculture, the growth of A375 cells was abrogated. The conventional CD25 + Treg cells, however, were unable to inhibit macrophage-mediated increase in tumor cell growth. Further analyses showed that Tr1 cells did not directly eliminate A375 cells, but mediated the killing of tumor-promoting macrophages through the secretion of granzyme B and perforin. The tumor-infiltrating interleukin 10 + Foxp3 − CD4 + T cells expressed very low levels of granzyme B and perforin, possibly suggested the downregulation of Tr1 cytotoxic capacity in melanoma tumors. Together, these data demonstrated an antitumor function of Tr1 cells through the elimination of tumor-promoting macrophages, which was not shared by conventional Tregs.

RETRACTION: Mechanism of MicroRNA-708 Targeting BAMBI in Cell Proliferation, Migration, and Apoptosis in Mice With Melanoma via the Wnt and TGF-β Signaling Pathways

“… 4 In cases of malignant melanoma, tumor-connected macrophages play many roles in connection to tumor growth, including its involvement in accelerating the transformation of melanocytes under ultraviolet irradiation, increasing melanoma angiogenesis, and acting to repress antitumor immunity. 5 The bone morphogenetic protein and activin membrane-bound inhibitor ( BAMBI ) is regarded to be a transmembrane TGF-β/BMP I receptor-associated pseudoreceptor. 6 The BAMBI and Drosophila mothers against decapentaplegic protein 7 (Smad7) have previously been reported to negatively regulate transforming growth factor-β (TGF-β) signaling as well as playing crucial roles in the progression of various malignant tumors.…”

Cytolytic Activity Score to Assess Anticancer Immunity in Colorectal Cancer

“…CAS-high tumors have more infiltration of activated memory CD4+ T cells whereas they did not for resting memory CD4+ T-cells or naïve CD4+ T-cells. This is likely secondary to re-activation of these CD4+ memory T-cells by tumor antigens resulting in stimulation of effector cytotoxic T cells and elevated CAS 28,29 . Gamma-delta T-cells are a subset of cytotoxic T-cells which produce TNF-α resulting in cell mediated lysis of tumor cells and had more infiltration into CAS-high tumors within our analysis 30 .…”

The Yin and Yang of Type 1 Regulatory T Cells: From Discovery to Clinical Application

“…The discovery of LAG3 and CD49b expressed on both murine and human memory CD4 + Tr1 cells enabled the isolation and characterization of Tr1 populations from peripheral blood of healthy donors (10). Since then, many other studies confirmed the expression of these proteins on murine (21)(22)(23)(24)(25)(26)(27)(28)(29), non-human primate (30) and human (18,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44) Tr1 cell populations.…”