Tumor Cell-Secreted ISG15 Promotes Tumor Cell Migration and Immune Suppression by Inducing the Macrophage M2-Like Phenotype

Abstract

Interferon-stimulated gene 15 (ISG15) is known to be involved in tumor progression. We previously reported that ISG15 expressed on nasopharyngeal carcinoma (NPC) cells and related to poor prognosis of patients with NPC. We further observed that ISG15 can be secreted by NPC cell and expressed on the macrophages in situ. However, the role of ISG15 in tumor-associated macrophages (TAMs) remains poorly understood. In the present study, we found that ISG15 treatment induces macrophages with M2-like phenotype, and the enhancement of NPC cell migration and tumorigenicity. Mechanically, ISG15-induced M2-like phenotype is dependent on the interaction with its receptor, LFA-1, and engagement of SRC family kinase (SFK) signal, and the subsequent secretion of CCL18. Blocking LFA-1, or SRC signal with small molecular inhibitors, or neutralizing with anti-CCL18 antibody can impede the activation of LFA-1-SFK-CCL18 axis in ISG15-treated macrophages. Clinically, ISG15+ CD163+ TAMs related to impaired survival of patients and advanced tumor stage of NPC. Furthermore, we found ISG15+ CD163+ macrophages inhibited antitumor CD8+ cells responses in NPC. Together, our findings suggested tumor cell-secreted ISG15, which acted as a tumor microenvironmental factor, induces M2-like phenotype, promoting tumor progression and suppression of cytotoxic T lymphocyte response.

Dendritic cell vaccines targeting tumor blood vessel antigens in combination with dasatinib induce therapeutic immune responses in patients with checkpoint-refractory advanced melanoma

“…Although ISG15 protein has been reported to serve as an effective adjuvant to vaccination, 68 it is also known to represent a biomarker of poor prognosis in the cancer setting 69 and to mediate pro-tumor immunoregulatory activity. 70 GSEA supported enhanced vascular-immune crosstalk, innate and adaptive immune cell presence, and antigen-presenting cell function in the TME of patients with IR/PR versus NIR/PD on trial ( online supplemental figure S11 ).…”

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

“…Monocytes from blood differentiate to M1 or M2 subtype macrophages, depending on their interactions with other cells present in tissues (Figures 6 and 7). Such differentiation is dependent on the environmental stimuli these cells are subject to (183)(184)(185)(186)(187)(188)(189)(190). The first type of antimicrobial macrophage activation became known as M1 macrophages (191).…”

Identification of novel key genes associated with the metastasis of prostate cancer based on bioinformatics prediction and validation

“…Meanwhile, ISG15 has been identified as a novel diagnostic biomarker of thyroid papillary microcarcinoma with lymphatic metastasis through proteomic analysis [ 28 ]. Further analysis has found that ISG15 could be secreted by nasopharyngeal carcinoma cells and induced macrophages to M2 polarization, thereby inhibiting the antitumor activity of T cells and accelerating tumor progression, indicating that ISG15 is an important molecule in tumor microenvironment [ 29 ]. However, ISG15 plays a role not only in promoting tumor progression but also in preventing tumor development.…”