Extracellular vesicles mediated proinflammatory macrophage phenotype induced by radiotherapy in cervical cancer

Abstract

Background Radiotherapy is a highly effective treatment for cervical cancer. Recent studies focused on the radiotherapy induced anti-tumor immunity. Whether tumor-derived extracellular vesicles (EVs) play roles in radiotherapy induced tumor associated macrophage (TAM) polarization remains unclear. Materials and Methods This study analysed the phenotype of macrophages in cancer tissue and peripheral blood of cervical cancer patients using flow cytometry analysis. The role of EVs from plasma of post-irradiated patients on M2-like transformed macrophages was assessed. The M1- and M2-like macrophages were assessed by expression of cell surface markers (CCR7, CD163) and intracellular cytokines (IL-10, TNFα and iNOS). The capacity of phagocytosis was assessed by PD-1 expression and phagocytosis of pHrodo Red E. coli bioparticles. Results Our results demonstrated that radiotherapy of cervical cancer induced an increase in the number of TAMs and a change in their subtype from the M2-like to the M1-like phenotype (increased expression of CCR7 and decreased expression of CD163). The EVs from plasma of post-irradiated patients facilitated the M2-like to the M1-like phenotype transition (increased expression of CCR7, TNFα and iNOS, and decreased expression of CD163 and IL-10) and increased capacity of phagocytosis (decreased PD-1 expression and increased phagocytosis of pHrodo Red E. coli bioparticles). Conclusions Our data demonstrated that irradiation in cervical cancer patients facilitated a proinflammatory macrophage phenotype which could eventually able to mediate anti-tumor immune responses. Our findings highlight the importance of EV in the crosstalk of tumor cells and TAM upon irradiation, which potentially leading to an increased inflammatory response to cancer lesions.

Identification of Immune and Hypoxia Risk Classifier to Estimate Immune Microenvironment and Prognosis in Cervical Cancer

“…Previous studies have uncovered the higher ratios of CD8+ to CD4+ T cells being closely related to improved survival [ 70 ]. On the contrary, the infiltration of neutrophils is proven to be positively correlated with survival of CC patients in our model, which is consistent with the common view that neutrophils are regarded as the most important leukocytes involving in first line defense to tissue damage [ 71 – 73 ]. Compared to the classic discipline to divide tumor immunophenotype into three subtypes (hot, altered, and cold), our finding compared the immune cell infiltration in high- and low-risk populations, may provide a more accurate model to guide the cellular based immunotherapy in CC.…”

The current understanding of the immune landscape relative to radiotherapy across tumor types

“…Radiotherapy can have stimulatory effects on the iTME as was seen in a prospective analysis of tumor-associated macrophages (TAMs) of patients treated with radical RT ( 110 ). A RT-dependent increase in the number of TAMs in cervical cancer tissue and a parallel shift towards the M1-like or pro-tumoral phenotypic state of macrophages (increased expression of CCR7 and decreased expression of CD163) was observed.…”

Macrophage-Derived Extracellular Vesicles: A Promising Tool for Personalized Cancer Therapy

“…Among several approaches carried out both to favor the oncosuppressive phenotype polarization and target TAMs specifically [ 16 ], the nanotechnological approach has proposed a heterogeneous nanoplatform composed of different drug delivery systems able to interact directly with TAMs and/or exploit their features with the aim of realizing efficacious anticancer therapies [ 17 , 18 , 19 ].…”