Modulation of Peripheral Immune Cell Subpopulations After RapidArc/Moderate Hypofractionated Radiotherapy for Localized Prostate Cancer: Findings and Comparison With 3D Conformal/Conventional Fractionation Treatment

Abstract

Radiotherapy (RT) is an important therapeutic option in patients with localized prostate cancer (PC). Unfortunately, radiation treatment causes a decrease in peripheral lymphocytes and, consequently, influences the patients’ immune status. Our aim was to study changes in peripheral blood immune cell subpopulations after RT and during 6 months’ follow-up in 2 groups of PC patients irradiated with different techniques and dose fractions with curative intent. We also investigated the presence of correlation between immune cell modulation and genitourinary or gastrointestinal toxicity. We enrolled 44 patients treated with curative RT (RapidArc/hypofractionation regimen or 3D conformal/conventional fractionation) for localized PC. Total white blood cell (WBC), absolute lymphocyte counts (ALCs), and peripheral immune cell subpopulations were analyzed at baseline, at the end of RT, and 3 and 6 months after the end of RT. WBC and ALC greatly decreased at the end of RT with a trend to recover at 6 months’ follow-up in the hypofractionation group but not in the conventional one. Furthermore, B, total T, T CD4+, T CD8+, and NK cell values dropped significantly in both groups at the end of RT, with a minor decrease detectable in the hypofractionation group for B, total T, and T CD4+ lymphocytes with respect to the other technique/fractionation group. Double-negative T (DNT), double-positive T (DPT), and NKT cells significantly decreased at the end of RT with a slight tendency to recover values during follow-up, particularly in the hypofractionation group. No correlation with genitourinary or gastrointestinal toxicity was found. In this study, we showed, for the first time, the effects of RapidArc/moderate hypofractionation RT on immune cell subsets in patients treated for localized PC. Due to the growing interest in minority T-cell subpopulations for immunotherapy, we also reported longitudinal monitoring of the effects of RT on DNT, DPT, and NKT, which was never studied before. Our preliminary data highlight the importance of considering the effects of different RT techniques/fractionation regimens on peripheral immune cells, in the era of RT and immunotherapy combination.

Radiotherapy-Related Gene Signature in Prostate Cancer

“…Clinical studies have also reported distant responses in patients receiving RT in combination with immune checkpoint inhibitors which were associated with alterations in circulating lymphocyte subsets and antibody responses to tumor-associated antigens [ 35 , 36 , 37 , 38 ]. In addition, there are studies to show changes in circulating immune cell subpopulations and cytokines in cancer patients after RT who did not receive systemic treatment [ 39 , 40 ]. However, so far there is no report to show an effect of RT on the expression of genes involved in immune regulation pathways affecting tumor progression which could further contribute to its immune-activating effects.…”

Preliminary analysis of double‐negative T, double‐positive T, and natural killer T‐like cells in B‐cell chronic lymphocytic leukemia

“…Very recently, our group performed a longitudinal monitoring of the RapidArc/moderate hypofractionation curative radiotherapy effects on the small subpopulations of T lymphocytes DNT, DPT, and NKT in patients treated for localized prostate cancer. DNT, DPT, and NKT cells significantly decreased at the end of RT with slight tendency to recover values during follow‐up, particularly in the hypofractionation group 51 …”

“…DNT, DPT, and NKT cells significantly decreased at the end of RT with slight tendency to recover values during follow‐up, particularly in the hypofractionation group. 51 …”

A review on lymphocyte radiosensitivity and its impact on radiotherapy

“…Because tumor-infiltrating lymphocytes appear to be quite radioresistant, differences in radiosensitivity between circulating lymphocytes and lymphocytes in lymphoid organs may have implications for lymphopenia and thus for considerations of dose prescription and dose scheduling in radiation therapy as well as for fractionation and scheduling of therapies involving both radiation and immune checkpoint inhibitors. An important aspect is also the influence of radiation dose distribution, delivery time and beam arrangement, which has been discussed in the context of highly conformal radiotherapy and its positive effect on lymphopenia ( 114 , 187 ).…”

“…The change in the ratio could not be explained by the small difference in radiosensitivities of CD4+ T cells and CD8+ T cells but was presumably caused by radiation-induced priming and mobilization of CD8+ T cells compensating for the loss of CD8+ T cells. Lymphocyte subpopulations in patients after radiation therapy have also been studied in other sites, such as in prostate cancer ( 42 , 114 – 116 ) and in breast cancer ( 117 , 118 ), demonstrating radiosensitivity of B cells in particular.…”