Journal Article

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

Tiersma, Jiske, Gordon‐Weeks, Alex N, Buzzelli, Jon, Muschel, Ruth J, Yuzhalin, Arseniy E, Im, Jae Hong, Jones, Keaton I

2018

Overview

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. Synopsis Increased CSF‐1 is here observed in response to tumour irradiation. Subsequent recruitment of immunosuppressive macrophages rendered the tumour microenvironment resistant to immune‐mediated tumour cell killing. Blocking CSF‐1 reduced tumour‐associated macrophages and increased sensitivity to immune checkpoint blockade. Irradiation stimulates CSF‐1 secretion by tumour cells. Immunosuppressive macrophages are increased in the tumour microenvironment after irradiation. Macrophage depletion via anti‐CSF permits CD8 + T‐cell‐mediated tumour cell killing. Macrophage depleted tumours are more sensitive to immune checkpoint blockade. Graphical Abstract Increased CSF‐1 is here observed in response to tumour irradiation. Subsequent recruitment of immunosuppressive macrophages rendered the tumour microenvironment resistant to immune‐mediated tumour cell killing. Blocking CSF‐1 reduced tumour‐associated macrophages and increased sensitivity to immune checkpoint blockade.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Adaptive immunity / Adaptive Immunity - radiation effects / Adaptive radiation / Animals / Antigens / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Colorectal Neoplasms - immunology / Colorectal Neoplasms - radiotherapy / Disease Models, Animal / EMBO03 / EMBO19 / Immune checkpoint / Immunosuppression / immunotherapy / Leukocyte Reduction Procedures / Lymphocytes T / macrophage / Macrophages / Macrophages - immunology / Mice / Pancreas / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - radiotherapy / PD-L1 protein / Phenotypes / radiation / Research Article / Treatment Outcome / Tumors / X-Ray Therapy