The Peripheral Myeloid Expansion Driven by Murine Cancer Progression Is Reversed by Radiation Therapy of the Tumor

Marka R Crittenden,Talicia Savage,Shelly Bambina,Benjamin Cottam,William L Redmond,Andrew M Jackson,Melissa Kasiewicz,Keith S Bahjat,Michael J Gough,Pippa Newell,Maria G Castro

doi:10.1371/journal.pone.0069527

Abstract

Expansion of myeloid-lineage leukocytes in tumor-bearing mice has been proposed as a cause of systemic immunosuppression. We demonstrate that radiation therapy of tumors leads to a decline in myeloid cell numbers in the blood and a decrease in spleen size. The frequency of myeloid cells does not decline to the level seen in tumor-free mice: we demonstrate that metastatic disease can prevent myeloid cell numbers from returning to baseline, and that tumor recurrence from residual disease correlates with re-expansion of myeloid lineage cells. Radiation therapy results in increased proliferation of T cells in the spleen and while T cell responses to foreign antigens are not altered by tumor burden or myeloid cell expansion, responses to tumor-associated antigens are increased after radiation therapy. These data demonstrate that myeloid cell numbers are directly linked to primary tumor burden, that this population contracts following radiation therapy, and that radiation therapy may open a therapeutic window for immunotherapy of residual disease.

Highlights

Myeloid cells have an important role in the development and progression of cancer
Despite the published suppressive effect of splenic myeloid cells ex vivo, these data demonstrate that the splenic myeloid expansion does not influence the degree or quality of the in vivo T cell response to L. monocytogenes-associated neoantigens. These data demonstrate that radiation therapy to the primary tumor significantly increases the vaccine directed response to antigens associated with the tumor. These data demonstrate that radiation therapy of the tumor halts the myeloid expansion associated with tumor growth, but this myeloid expansion is restored following recurrence of the primary tumor (Figure 1)
Myeloid numbers do not return to baseline following radiation therapy, but remain elevated due to the contribution of residual local and metastatic disease, and myeloid contraction in the blood is matched in the spleen (Figure 2)

Summary

Introduction

Myeloid cells have an important role in the development and progression of cancer. Tumor-associated macrophages are critical for angiogenesis, invasion, metastasis, immunosuppression and response to therapy [1,2,3]. Gemcitabine and 5-FU chemotherapy have been shown to control the myeloid expansion in the spleens of tumor-bearing mice [9,10,11] Each of these agents has been described to have a direct inhibitory effect on myeloid populations in vitro [10,11]. It is interesting that this effect is incomplete, as cells do not return to naıve levels These data suggest that tumors have an effect on myeloid cells that persists beyond excision. In this model the effect of tumor excision is transient, as myeloid expansion returns with recurrence of the primary tumor and metastases [12] These data could be reinterpreted to suggest that residual cancer cells may prevent a full normalization of myeloid numbers. This trauma-induced myeloid expansion may conceal the extent of the reduction in myeloid cells caused by surgical removal of the primary tumor, and add to any myeloid expansion sustained by residual disease

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Conclusion