Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade

Abstract

Emerging evidence suggests a role for radiation in eliciting anti‐tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony‐stimulating factor 1 (CSF‐1). Coincident with the elevation in CSF‐1, macrophages increased in tumours, peaking 5 days following irradiation. These tumour‐associated macrophages (TAMs) were skewed towards an immunosuppressive phenotype. Macrophage depletion via anti‐CSF (aCSF) reduced macrophage numbers, yet only achieved tumour growth delay when combined with radiation. The tumour growth delay from aCSF after radiation was abrogated by depletion of CD8 T cells. There was enhanced recognition of tumour cell antigens by T cells isolated from irradiated tumours, consistent with increased antigen priming. The addition of anti‐PD‐L1 (aPD‐L1) resulted in improved tumour suppression and even regression in some tumours. In summary, we show that adaptive immunity induced by radiation is limited by the recruitment of highly immunosuppressive macrophages. Macrophage depletion partly reduced immunosuppression, but additional treatment with anti‐PD‐L1 was required to achieve tumour regression.

Characteristics of Tumor Immune Gene and Immune Cell Infiltration during Keloid Formation

“…Products of T1 and T2 responses (e.g., IFNγ and IL-4) also downregulate M2 and M1 activity, respectively [34]. Thus, M1/M2 proportion demonstrated the importance of innate immunity, and how it is linked to adaptive immunity in a beautifully counterbalanced system [35,36].…”

Ping-Pong—Tumor and Host in Pancreatic Cancer Progression

“…TAM mostly exhibit the suppressive phenotype of CD163+ and CD204+ M2 (650, 651), M2 differentiation being supported by tumorand Treg-derived IL4, IL10, and IL13 (652). TAM suppress the adaptive immune response via TGFβ, IL10, CCL17, CCL18, CCL22, and PDL1 1 secretion (653,654). In addition, CCL2 and CCL20 1 through chemokine receptor CCR6 1 binding promote MMP9 upregulation and thereby invasiveness (655,656) and can contribute to EMT (657,658).…”

“…CCL2 and SDF1 support MDSC recruitment, GM-CSF plays a major role in inflammatory milieu maintenance (667). Prominent signaling molecules engaged in MDSC activity are STAT3, COX2, HIF1α, C/EBPB 1 , HMOX1 1 , and IDO 1 (654,670,671). MDSC interfere at several levels with immune response induction (672).…”

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

“…However, abundance of highly immunosuppressive macrophages upon irradiation has recently been described as well [90][91][92]. A murine study by Jones et al [93] has recently observed that TAM may be polarized towards either suppressive or stimulatory phenotypes upon irradiation depending on the type of cancer. Reducing macrophage recruitment into the tumor microenvironment by colony-stimulating factor-1 (CSF-1) blocking antibodies [94] led to an increased abundance of M1 polarized macrophages in the tumor.…”

“…Tumor-associated macrophages often constitute a major immunosuppressive cell lineage in the context of cancer [86]. In a murine xenograft model of irradiation, a PD-1 blockade combination with an induced colony-stimulating factor 1 (CSF-1) inhibitor significantly reduced external beam radiation-associated repopulation of the tumor microenvironment with macrophages and led to potent synergy due to the lack of immunosuppressive signaling from macrophages [93].…”