LAUSR

The novel human Coronavirus (SARS-CoV-2) pandemic started in late 2019 has killed more than 1 million people worldwide (1). The fatality rate has been linked with a hyperinflammation state dependent of human interleukin-6 levels and a cytokine-release syndrome (2). This proinflammatory micro-environment can induce lymphocyte-deficiency via apoptosis, impairing immune-homeostasis, and inflammatory-response (3). Indeed, lymphopenia has emerged as a major predictor of severe COVID-19 (3). A lymphocyte count <1.5 × 10/L has been associated with a three-fold increased risk of severe COVID-19 (4). Noteworthy, lymphocytes express AngiotensinConverting Enzyme 2 (ACE2) receptor which is exploited by the SARS-CoV-2 to enter host targetcells, thus representing a possible virus direct target with a subsequent, potentially lethal, lymphatic organs attack (3). Cancer treatments can often suppress reservoir lymphoid organs causing lymphopenia, which is associated with an increased risk of opportunistic infections and worse oncologic outcomes due to the lymphocytes essential role within the anti-tumor immune response (5). Although chemotherapy (CT) is often the main trigger of hematologic toxicity (HT), radiotherapy is also a contributing factor for impairment of hematologic cell lines (6, 7). Lymphocytes are extremely radiosensitive and show exponential decline early and throughout irradiation (8). The lethal dose required to reduce the surviving fraction of lymphocytes by 50% (LD50) is only 1.5 Gy, and by 90% (LD90), 3 Gy (9). Radiation-induced lymphopenia (RIL) has been reported to negatively affect prognosis in several neoplasms including non-small cell lung cancer (NSCLC), glioblastoma, pancreatic cancer, esophageal cancer, and head and neck cancers (10–19). Lee et al. evaluated RIL in a cohort of 497 locally advanced pancreatic cancer patients treated with chemoradiation (10). Large radiotherapy volumes and low baseline lymphocyte count predicted for acute severe lymphopenia development and recovery. The authors highlighted the importance of severe acute lymphopenia as it was associated with both poorer overall survival (OS) and progression-free survival (PFS) (10). For NSCLC, Jin et al. considered the immune system as an organ-at-risk in the radiotherapy planning. The estimated dose of radiation to circulating immune cells (EDRIC) model was developed, and a higher EDRIC was associated with not only a greater risk of grade 3 or worse lymphopenia but also with poorer oncological outcomes (tumor progression and cancer deaths) within the RTOG-0617 study (12, 13). Tang et al. reported a significant association between lung low-dose exposure (V1-V5), involving the pulmonary vasculature circulating lymphocytes, and lymphopenia degree (14). For esophageal cancers, So et al. found that a low lymphocyte nadir was predictor for OS (hazard ratio = 0.63; p < 0.001) (16). The authors highlighted a significant correlation between radiation dose to circulating immune cells and the lymphocytes nadir (16).