M2 macrophages are more resistant than M1 macrophages following radiation therapy in the context of glioblastoma

Abstract

In some highly inflammatory tumors, such as glioblastoma (GB), macrophages (MΦ) represent the most abundant population of reactive cells. MΦ, initially denoted as M0 MΦ, can be polarized into two further phenotypes: the antitumor M1 MΦ, and the protumor M2 MΦ. The three phenotypes can reside simultaneously in the tumor mass and various external factors may influence MΦ polarization. Radiotherapy is a common modality of cancer treatment aiming to target tumor cells. However, the specific effects of X-ray radiation on the inflammatory cells are, so far, controversial and not fully understood. In the present investigation, we have first analyzed, in vivo, the effect of X-ray radiation on MΦ present in GB tumors. We have observed a decrease in MΦ number paralleled by an increase in the proportion of M2 MΦ. To understand this phenomenon, we then evaluated, in vitro, the effects of X-rays on the MΦ phenotypes and survival. We have found that X-ray radiation failed to modify the phenotype of the different MΦ. However, M1 MΦ were more sensitive to ionizing radiation than M2 MΦ, both in normoxia and in hypoxia, which could explain the in vivo observations. To conclude, M2 MΦ are more radioresistant than M0 and M1 MΦ and the present study allows us to propose that X-ray radiotherapy could contribute, along with other phenomena, to the increased density in the protumor M2 MΦ in GB.

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…(2) TAMs that are recruited can either polarize into a continuum of macrophage states that are described with two extremes: an M1 (2a) or an M2 (2b) phenotype depending on the signal they receive (IFNg/LPS/GM-CSF for M1 and IL-4/IL-13/M-CSF for M2) Pyonteck et al, 2013;Kast et al, 2017;Roesch et al, 2018. (3) M1-like TAMs are macrophages with anti-tumor properties such as tumor cell kill abilities mediated by the production of NO, ROS, IFNg Kennedy et al, 2013;Leblond et al, 2017. They also mediate the Th1 response in the tumor through the activation of Th helper cells by secreting CXCL9, CXCL10, IL-12 Poon et al, 2017.…”

“…TAMs participate in the induction of GB cell differentiation to a mesenchymal state through NF-kB production, an event that correlated with radiation resistance (Bhat et al, 2013). Recently, Leblond et al showed that M1 macrophages are more sensitive to radiation than M2 macrophages (Leblond et al, 2017). The proportion of M2 macrophages in irradiated tissues is thus increased.…”

Macrophages in radiation injury: a new therapeutic target

“…8 It seems that anti-inflammatory macrophages are more radio-resistant than proinflammatory macrophages. 27 Our study clearly showed that interstitial and alveolar macrophages were modulated differently during the acute phase of IR response (Figure 1); interestingly, 15 days post-IR AMs were depleted but not IMs, suggesting that IMs are more radio-resistant than AMs. 8 Furthermore, IMs are profibrosant but not AMs.…”

ATM-mediated DNA damage response in macrophages primes phagocytosis and immune checkpoint regulation

“…Recently, it has been suggested that in numerous chemotherapy regimens the induction of innate and adaptive immune responses towards malignant cells significantly contribute to anti-tumor outcomes (1,17,18). Radiation-induced changes in macrophages include M2-like polarization and have been associated with disease progression (19)(20)(21). Chemotherapy also increases the immunogenicity of malignant cells and disrupts immunosuppressive circuitries in the tumor microenvironment (1,22).…”