Differential Association Between Circulating Lymphocyte Populations With Outcome After Radiation Therapy in Subtypes of Liver Cancer

Purpose: Irradiation may have significant immunomodulatory effects that impact tumor response and could potentiate immunotherapeutic approaches. The purposes of this study were to prospectively investigate circulating lymphoid cell population fractions during hypofractionated proton therapy (HPT) in blood samples of liver cancer patients and to explore their association with survival. Methods and Materials: We collected serial blood samples before treatment and at days 8 and 15 of HPT from 43 patients with liver cancer—22 with hepatocellular carcinoma (HCC) and 21 with intrahepatic cholangiocarcinoma (ICC)—enrolled in a phase 2 clinical trial. All patients received 15 fractions of proton therapy to a median dose of 58 Gy (relative biological effectiveness). We used flow cytometry to measure the changes in the fractions of total CD3 ⁺ , CD4 ⁺ , and CD8 ⁺ T cells; CD4 ⁺ CD25 ⁺ T cells; CD4 ⁺ CD127 ⁺ T cells; CD3 ⁺ CD8 ⁺ CD25 ⁺ activated cytotoxic T lymphocytes (CTLs); and CD3 ^– CD56 ⁺ natural killer cells. Results: With a median follow-up period of 42 months, median overall survival (OS) in the study cohort was 30.6 months for HCC and 14.5 months for ICC patients. Longer OS was significantly correlated with greater CD4 ⁺ CD25 ⁺ T-cell (P = .003) and CD4 ⁺ CD127 ⁺ T-cell (P = .01) fractions at baseline only in ICC patients. In HCC patients, the fraction of activated CTLs mid treatment (at day 8) was significantly associated with OS (P = .007). These findings suggest a differential relevance of immunomodulation by HPT in these liver cancers. Conclusions: Antitumor immunity may depend on maintenance of a sufficiently high number of activated CTLs during HPT in HCC patients and CD4 ⁺ CD25 ⁺ T cells and CD4 ⁺ CD127 ⁺ T cells prior to treatment in ICC patients. These results could guide the design of future studies to determine the optimal treatment schedules when combining irradiation with specific immunotherapy approaches.