Galectin-1 inhibits the viability, proliferation, and Th1 cytokine production of nonmalignant T cells in patients with leukemic cutaneous T-cell lymphoma

Abstract

Tumor-derived galectin-1 (Gal-1), a ␤-galactoside-binding S-type lectin, has been shown to encourage T-cell death and promote T cell-mediated tumor immune escape. In this report, we show that patients with leukemic cutaneous T-cell lymphomas, known to have limited complexity of their T-cell repertoires, have a predominant T helper type-2 (Th2) cytokine profile and significantly elevated plasma levels of Gal-1 compared with healthy controls. Circulating clonal malignant T cells were a major source of Gal-1. IntroductionContraction of the T-cell repertoire and Th2 cytokine skewing are 2 immunosuppressive features linked to high morbidity and mortality of patients with leukemic cutaneous T-cell lymphoma (L-CTCL). [1][2][3][4][5] Certain soluble factor(s) expressed by clonal malignant cells or dermal fibroblasts (eg, IL-18, eotaxins) could be responsible for this immunologic signature; nevertheless, mechanistic evidence on how these cells elicit their immunoregulatory function is still incomplete. 6,7 Recently, the ␤-galactoside binding protein, galectin-1 (Gal-1), has been implicated in the induction of a Th2 signature and suppression of antitumor immune responses in patients with Hodgkin lymphoma. 8,9 Gal-1 functions as a homodimer with affinity for N-acetyllactosamine-bearing glycoproteins on effector T cells that, on engagement, induces proapoptotic and/or immunosuppressive activities. 10,11 Gal-1-binding interactions induce deletion of pro-inflammatory T helper (Th)-1 and Th17 cells but spare naive, regulatory, and Th2 cells, leading to a tolerogenic environment that favors tumor immune escape. 12,13 Indeed, in patients with Hodgkin disease, increased Gal-1 expression is correlated with poor prognoses and implicated as a biomarker of disease progression. 14 Although a prior study shows that Gal-1 expression is elevated in epidermotropic malignant T cells in patients with mycosis fungoides, 15 its presence and role in more advanced leukemic forms of CTCL have not been addressed. Here we show that clonal malignant T cells in patients with stage 3 or 4 CTCL exhibited a Th2 cytokine signature and high intracellular Gal-1 expression. Moreover, L-CTCL patients exhibited higher plasma Gal-1 levels than healthy controls, and conditioned supernatants from primary L-CTCL cell cultures significantly attenuated normal T-cell proliferation and diminished Th1 responses in a ␤-galactosidedependent manner. Collectively, these data suggest that elevated levels of Gal-1 in L-CTCL patients may inhibit the proliferation of nonmalignant T cells and favor Th2 skewing, leading to impaired antitumor responses and increased susceptibility to infection. These studies suggest that neutralization of Gal-1-Gal-1 ligand interactions may be an effective strategy for enhancing antitumor immune responses in L-CTCL patients. Methods PBMCs and plasma samplesAll studies were performed in accordance with the Declaration of Helsinki and approved by the review board of the Partners Human Research Committee. PBMCs and plasma were obtained using Fico...

PLCG1 mutations in cutaneous T-cell lymphomas

“…It is of note that many of the mutations we have detected in our mutational study affect signaling molecules such as CCR4, IL6S/T, and JAK proteins or those affecting the NFkB pathway that have been shown to regulate the acquisition of a Treg or a Th17 phenotype. 10 Interestingly, our data could provide a mechanistic explanation for the nature of the phenotypic plasticity that other researchers have seen in human CTCL samples [5][6][7]9 Although the exact contribution of these altered phenotypes to the pathogenesis of CTCL requires further attention, our mutational results strongly suggest that a number of genes and signaling pathways known to mechanistically control critical T-cell biological activities, including proliferation, survival, and differentiation, are recurrently targeted by somatic mutations in human MF/SS samples. This reveals potential targets for the development of new therapeutic strategies we can now begin to explore.…”

“…Gene expression profiling studies have shown that increased signaling from the TCR can be considered a driving force of CTCL and that neoplastic T cells can show a degree of phenotypic plasticity, as characterized by the expression of a variety of lineage markers. [5][6][7][8][9] However, whether this is the result of signaling from the tumor stroma or the consequence of specific genetic alterations in the pathways involved in TCR signaling is still a matter of active research. [10][11][12] Early stages of CTCL are treated with combinations of UV and immunotherapy, with mono-or polychemotherapy being reserved for cases that do not respond to previous treatment.…”

Presence of galectin-1 in the epidermal and dermal thickening of keloid tissues

“…It is important to highlight that in the keratinocytes from normal adult skin, Gal-1 was not evidenced. Remarkably, previous studies in human skin have shown that Gal-1 is not expressed by keratinocytes in normal skin [37] but can be expressed by cells in psoriasis [37,38], cutaneous malignant lesions including squamous cell carcinoma [39], mycosis fungoides [40,41], and melanoma [42], while in keloid tissues, proteome analysis of keloid proteins performed by Ong et al revealed that the expression of Gal-1 is upregulated compared to normal skin [43]. However, the role of Gal-1 in skin lesions is still unclear.…”

“…Gal-1, like others galectins, participates in signaling pathways and regulates a variety of biological responses including cell growth, cell-cell and cell-matrix adhesion, cell differentiation, migration, proliferation and survival [31][32][33][34] and plays a critical role in inflammation, angiogenesis, and tumor development and progression [27,33,35,36]. In human skin, Gal-1 has been implicated in psoriasis [37,38] and malignant lesions including cutaneous cancer [39], mycosis fungoides [40,41], and melanoma [42], and scarce studies have shown that the expression of Gal-1 is upregulated in keloid tissue [43]. However, the presence, distribution, and localization of Gal-1 as well as its possible role in benign dermal fibroproliferative tumors such as keloids, have not been completely elucidated.…”

Knockdown of galectin-1 suppresses the growth and invasion of osteosarcoma cells through inhibition of the MAPK/ERK pathway

“…Targeting GAL1 in carcinoma-associated fibroblasts inhibits oral squamous cell carcinoma metastasis by downregulating MCP-1/CCL2 expression (18). However, some reports show GAL1 inhibits the viability, proliferation and Th1 cytokine production of non-malignant T cells in patients with leukemic cutaneous T-cell lymphoma (19), and GAL1 silencing imparts colorectal cancer with the ability to proliferate and escape apoptosis (20). Further research suggests that GAL1 plays vital pro-tumorigenic roles within the tumor microenvironment (21), and stimulates the proliferation of melanoma and neo-angiogenesis processes (22).…”