The effects of radiation therapy on the macrophage response in cancer

Abstract

The efficacy of radiotherapy, a mainstay of cancer treatment, is strongly influenced by both cellular and non-cellular features of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are a heterogeneous population within the TME and their prevalence significantly correlates with patient prognosis in a range of cancers. Macrophages display intrinsic radio-resistance and radiotherapy can influence TAM recruitment and phenotype. However, whether radiotherapy alone can effectively “reprogram” TAMs to display anti-tumor phenotypes appears conflicting. Here, we discuss the effect of radiation on macrophage recruitment and plasticity in cancer, while emphasizing the role of specific TME components which may compromise the tumor response to radiation and influence macrophage function. In particular, this review will focus on soluble factors (cytokines, chemokines and components of the complement system) as well as physical changes to the TME. Since the macrophage response has the potential to influence radiotherapy outcomes this population may represent a drug target for improving treatment. An enhanced understanding of components of the TME impacting radiation-induced TAM recruitment and function may help consider the scope for future therapeutic avenues to target this plastic and pervasive population.

Neutrophils seeking new neighbors: radiotherapy affects the cellular framework and the spatial organization in a murine breast cancer model

“…Regarding macrophages, Leblond et al [ 57 ] reported that pro-tumoral M2 macrophages are more resistant to RT that M1 macrophages in the context of glioblastoma. Macrophage polarization by irradiation, however, has also been described dependent on the irradiation dose and scheme [ 13 ]. In our model we cannot distinguish between pro- and anti- tumoral neutrophils or M1 and M2 macrophages.…”

“…The polarization of macrophages has been shown to be inducible by irradiation. Dependent on the irradiation dose and scheme the cells are either polarized toward M1 or M2 [ 13 , 14 ]. However, the identification of polarized macrophages in situ remains a major challenge [ 15 ].…”

Dual effects of radiotherapy on tumor microenvironment and its contribution towards the development of resistance to immunotherapy in gastrointestinal and thoracic cancers

“…After irradiation, the accumulation of MDSCs in the tumor stroma was found to be elevated ( Lehmann et al, 2008 ). Furthermore, radiation altered the expression levels of TAM-produced chemokines, thereby altering the regulation of T-cell infiltration in cancer tissues ( Inoue et al, 2004 ; Beach et al, 2022 ). However, it is warranted to clarify how the TME is involved in the regulation of radiation-induced TAM recruitment and which MDSC and TAM cell populations should be targeted to improve the anti-cancer treatment.…”

Tumour-associated macrophages as a potential target to improve natural killer cell-based immunotherapies

“…However, they can increase tumour cell susceptibility to NK cells and create a favourable environment for “transferred” NK cells, which may benefit NK cell-infusion therapy [ 78 , 79 ]. Moreover, chemotherapy and radiotherapy can change the phenotype of TAMs to be immunostimulatory [ 80 , 81 ], although their effects on NK cell functions are unknown. Moreover, the response of the TME to chemotherapy and radiation could vary in individual cases.…”