Abstract
The immune system plays a vital role in cancer therapy, especially with the advent of immunotherapy. Radiation therapy induces iatrogenic immunosuppression referred to as radiation-induced lymphopenia (RIL). RIL correlates with significant decreases in the overall survival of cancer patients. Although the etiology and severity of lymphopenia are known, the mechanism(s) of RIL are largely unknown. We found that irradiation not only had direct effects on circulating lymphocytes but also had indirect effects on the spleen, thymus, and bone marrow. We found that irradiated cells traffic to the bone marrow and bring about the reduction of hematopoietic stem cells (HSC) and progenitor cells. Using mass cytometry analysis (CyTOF) of the bone marrow, we found reduced expression of CD11a, which is required for T cell proliferation and maturation. RNA Sequencing and gene set enrichment analysis of the bone marrow cells following irradiation showed down-regulation of genes involved in hematopoiesis. Identification of CD11a and hematopoietic genes involved in iatrogenic immune suppression can help identify mechanisms of RIL.
Highlights
The immune system plays an important role in keeping us healthy from pathogens and foreign bodies including cancer cells
After irradiation to the thorax, we found a significant reduction in the circulating CD3 (4.18E+02 vs. 9.00E+01; P ≤ 0.0001), CD4 (2.59E+02 vs. 6.06E+01; P ≤ 0.0001), CD8 (9.14E+01 vs. 1.36E+01; P = 0.011) and CD19 (3.58E+02 vs. 7.99E+01; P ≤ 0.0001) cells in the blood (Figure 1B)
After irradiation to the head, we found a significant reduction in the circulating CD3 (3.71E+02 vs. 7.64E+01; P ≤ 0.0001), CD4 (1.88E+02 vs. 4.63E+01; P ≤ 0.0003), CD8 (1.37E+02 vs. 1.51E+01; P = 0.0012) and CD19 (3.08E+02 vs. 9.23E+01; P ≤ 0.0001) cells in the blood (Figure 1C)
Summary
The immune system plays an important role in keeping us healthy from pathogens and foreign bodies including cancer cells. Immune system plays an important role in cancer therapy especially with the advent of immunotherapy [1]. RIL is associated with poor outcome for many cancers, including lung, colon, pancreas, and breast [2,3,4]. Previous studies have implicated the direct effects of radiation on lymphocyte depletion [5, 6]. Direct damage to the T-cells from radiation will reduce the number of T-cells in circulation which should be repopulated in 80– 90 days. RIL persists six months to a year after irradiation [3, 7] which is far beyond the T-cell turnover time suggesting an indirect mechanism may be involved in immune suppression
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