A review on lymphocyte radiosensitivity and its impact on radiotherapy

Abstract

It is well known that radiation therapy causes lymphopenia in patients and that this is correlated with a negative outcome. The mechanism is not well understood because radiation can have both immunostimulatory and immunosuppressive effects. How tumor dose conformation, dose fractionation, and selective lymph node irradiation in radiation therapy does affect lymphopenia and immune response is an active area of research. In addition, understanding the impact of radiation on the immune system is important for the design and interpretation of clinical trials combining radiation with immune checkpoint inhibitors, both in terms of radiation dose and treatment schedules. Although only a few percent of the total lymphocyte population are circulating, it has been speculated that their increased radiosensitivity may contribute to, or even be the primary cause of, lymphopenia. This review summarizes published data on lymphocyte radiosensitivity based on human, small animal, and in vitro studies. The data indicate differences in radiosensitivity among lymphocyte subpopulations that affect their relative contribution and thus the dynamics of the immune response. In general, B cells appear to be more radiosensitive than T cells and NK cells appear to be the most resistant. However, the reported dose-response data suggest that in the context of lymphopenia in patients, aspects other than cell death must also be considered. Not only absolute lymphocyte counts, but also lymphocyte diversity and activity are likely to be affected by radiation. Taken together, the reviewed data suggest that it is unlikely that radiation-induced cell death in lymphocytes is the sole factor in radiation-induced lymphopenia.

Keywords: blood dose; lymphocytes; lymphopenia; radiosensitivity; radiotherapy.

Figure 1

Radiosensitivity of lymphocyte sub-populations in mice for studies shown in Table 2B . First row: Splenocytes, B cells, and NK cells. Second row: Combined T cells and T_cyt cells. Third row: T_h cells and T_reg cells. Data points are shown up to 5 Gy but alpha value fits were only done for data points ≤3 Gy because lymphocytes will not receive more than the prescription dose in a single fraction in radiation therapy, and because the majority of the dose-response data show a more shallow slope and a saturation at higher doses. The data points were extracted from the published figures (using plotdigitizer (plotdigitizer.com)). Experimental error bars are not shown but are included in the fits (performed using LMfit in python).

Figure 2

Radiosensitivity of peripheral lymphocytes, NK cells, T cells, and B cells. Data are grouped to illustrate both, differences between experiments as well as differences between subpopulations. Data points are shown up to 5 Gy but alpha values fits include only data points ≤ 3 Gy because lymphocytes will not receive more than the prescription dose in a single fraction in radiation therapy, and because the majority of the dose-response data show a more shallow slope and a saturation at higher doses. The data points were extracted from the published figures (using plotdigitizer (plotdigitizer.com)). Experimental error bars are not shown but are included in the fits (performed using LMfit in python).