Targeting protumor factor chitinase-3-like-1 secreted by Rab37 vesicles for cancer immunotherapy

Abstract

Background: Chitinase 3-like-1 (CHI3L1) is a secretion glycoprotein associated with the immunosuppressive tumor microenvironment (TME). The secretory mode of CHI3L1 makes it a promising target for cancer treatment. We have previously reported that Rab37 small GTPase mediates secretion of IL-6 in macrophages to promote cancer progression, whereas the roles of Rab37 in the intracellular trafficking and exocytosis of CHI3L1 are unclear. Methods: We examined the concentration of CHI3L1 in the culture medium of splenocytes and bone marrow derived macrophages (BMDMs) from wild-type or Rab37 knockout mice, and macrophage or T cell lines expressing wild type, active GTP-bound or inactive GDP-bound Rab37. Vesicle isolation, total internal reflection fluorescence microscopy, and real-time confocal microscopy were conducted. We developed polyclonal neutralizing-CHI3L1 antibodies (nCHI3L1 Abs) to validate the therapeutic efficacy in orthotopic lung, pancreas and colon cancer allograft models. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37 and CHI3L1, and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from cancer patients. Results: We demonstrate a novel secretion mode of CHI3L1 mediated by the small GTPase Rab37 in T cells and macrophages. Rab37 mediated CHI3L1 intracellular vesicle trafficking and exocytosis in a GTP-dependent manner, which is abolished in the splenocytes and BMDMs from Rab37 knockout mice and attenuated in macrophage or T cell lines expressing the inactive Rab37. The secreted CHI3L1 activated AKT, ß-catenin and NF-κB signal pathways in cancer cells and macrophages to foster a protumor TME characterized by activating M2 macrophages and increasing the population of regulatory T cells. Our developed nCHI3L1 Abs showed the dual properties of reducing tumor growth/metastases and eliciting an immunostimulatory TME in syngeneic orthotopic lung, pancreas and colon tumor models. Clinically, high plasma level or intratumoral expression of CHI3L1 correlated with poor survival in 161 lung cancer, 155 pancreatic cancer and 180 colon cancer patients. Conclusions: These results provide the first evidence that Rab37 mediates CHI3L1 secretion in immune cells and highlight nCHI3L1 Abs that can simultaneously target both cancer cells and tumor microenvironment.

The Upregulation of GSTO2 is Associated with Colon Cancer Progression and a Poor Prognosis

“…Tere have been several studies on colon cancer. associated with the TME, could be a target for cancer therapy [47]. TME plays an important role in nanodrugs and immunotherapy [48,49].…”

“…Sanchez-Lopez et al pointed out that the tumor microenvironment (TME) exerts critical protumorigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility, and invasion [ 46 ]. Yang et al demonstrated that CHI3L1, a secretory glycoprotein associated with the TME, could be a target for cancer therapy [ 47 ]. TME plays an important role in nanodrugs and immunotherapy [ 48 , 49 ].…”

Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming

“…In non-muscle cells, actin filaments form a track system to transport cargo such as vesicles and organelles. Recently, it was reported that Rab37 mediated CHI3L1 intracellular vesicle trafficking and exocytosis 44 . Actually, F-actin and the F-actin assembly pathway regulate exocytosis 45 .…”

Recent advances in conventional and unconventional vesicular secretion pathways in the tumor microenvironment

“…Moreover, Rab37 mediates intracellular vesicle trafficking and exocytosis of chitinase 3-like-1 (CHI3L1), a protumor secretion glycoprotein associated with the immunosuppressive TME, in a GTP-dependent manner which is abolished in the splenocytes and macrophages from Rab37 KO mice. The secreted CHI3L1 activates AKT, β-catenin and NF-κB signal pathways in cancer cells and elicits a protumor TME characterized by activating M2 macrophages and increasing the population of regulatory T cells [75] (exocytosis, Fig. 3A).…”

“…Importantly, Rab37 colocalizes with IL-2 at the immune synapse, while it colocalizes with TNF in the cytoplasmic compartment in Th1 cells [97]. Of note, Rab37 has recently shown to regulate exocytotic secretion of pro-tumor glycoprotein CHI3L1 from T cell in a GTP-dependent manner to activate M2 macrophages and increase the population of regulatory T cells via activating AKT, β-catenin and NF-kB signal pathways in TME of lung, pancreatic and colon cancers [75] (exocytosis, Fig. 3B).…”