Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma

Abstract

Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1. EVs suppress proliferation of CD4 + and CD8 + T-cells in vitro and in vivo in OvCa mouse models. In mice, ARG1-containing EVs are transported to draining lymph nodes, taken up by dendritic cells and inhibit antigen-specific T-cell proliferation. Increased expression of ARG1 in mouse OvCa cells is associated with accelerated tumor progression that can be blocked by an arginase inhibitor. Altogether, our studies show that tumor cells use EVs as vehicles to carry over long distances and deliver to immune cells a metabolic checkpoint molecule – ARG1, mitigating anti-tumor immune responses.

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

“…Further studies by Liu and colleagues reported that also mice glioblastoma cells-EVs promote in vivo tumor cell growth by inhibiting CD8+T cell cytolytic activity [57]. In more recent studies, Maybruck and colleagues correlated the EV-mediated dysfunction of CD8+T cells, in head and neck cancer, with the presence of the immunoregulatory protein, galectin-1 [58], while in ovarian carcinoma, tumor EVs inhibit the proliferation of CD4+ and CD8+ T cells by delivering the metabolic checkpoint molecule arginase-1 [59]. One of the major mechanisms by which tumor cells can inhibit CD8+ T cell functions is correlated with activation of immune checkpoints as that mediated by the PD-1/PD-L1 pathway.…”

Pathophysiological Role and Potential Therapeutic Exploitation of Exosomes in Ovarian Cancer

“…Another role of ascites-derived exosomes is to serve as the immunosuppressor. Arginase-1 (ARG1)-carrying exosomes accelerate ovarian cancer growth by suppressing T-cells Phosphatidylserine in ascites inhibits T-cell activity and Fas ligand induces the apoptosis of T-cells [41][42][43] Labani-Motlagh et al reported that phosphatidylserine, natural-killer receptor group 2, member D (NKG2D) and DNX accessory molecule-1 (DNAM-1) ligands in ascites-derived exosomes inhibited NK cell activity, resulting in immune suppression [40]. As described above, exosomes contribute to multiple steps during invasive processes and to early steps in peritoneal dissemination and metastasis.…”

“…Thereafter, CAF-derived exosomes promote epithelial-mesenchymal transition to ovarian cancer cells[48,49]. (4) Ovarian cancer cell-derived exosomes inhibit immune cells and facilitates the conversion of macrophages to tumor-associated macrophages[38,[40][41][42]44,45]. (B) The involvement of exosomes in peritoneal dissemination (5).…”

Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion

“…Indeed, the ability of many soluble protein-dependent mechanisms to alter distant DC function such as in draining lymph node tissues is more limited. The recent realization that tumor-derived exosomes are capable of genetically altering distant immune cell populations implies that these extracellular vesicles and their molecular cargo are likely to be very important players in DC tolerization and tumor-mediated immune evasion (54,55,77).…”