Treatment Induced Changes in Systemic Immune Environment in Patients with Unresectable Hepatocellular Carcinoma

Abstract

<h3>Purpose/Objective(s)</h3> Host immune status plays an essential role in cancer patients. However, it is unknown whether therapy can change or remodel this environment which can influence treatment response to the remaining treatment. It is unknown however whether such change varies with treatment modality. This study aimed to exam the systemic immune status, explore the changes after arterial chemotherapy embolization (TACE), stereotactic body radiation therapy (SBRT) and immunotherapy (IO) as well as their correlation with treatment responses in patients with hepatocellular carcinoma (HCC). <h3>Materials/Methods</h3> This is a pilot study of correlative research for a prospective phase II trial. Patients with unresectable HCC were eligible. The protocol treatment included sequential TACE, SBRT (27.5–40 Gy/5 fractions) and IO. TACE and SBRT were per standard of care. Treatment response was assessed according to mRECIST by CT or MRI around 6 months from treatment commencement. Peripheral blood samples were collected at baseline and after TACE, SBRT and IO for lymphocyte subtypes of our interest by flow cytometry, including NKT cell, T, CD4+T, CD8+T, CD25+CD8+T, CD127+CD8+T, Th1, Th2, Th17, Treg, CD4/CD8 T cell, Th2/Th1, Th1/Th17 and Th17/Treg. Generalized estimation equation was employed for longitudinal analyses, and Bonferroni adjustment for multiple testing was performed for statistical significance at a p < 0.0083 (0.05/6) level. <h3>Results</h3> A pilot of 12 patients were enrolled between July 2020 and February 2021, with Child Pugh score of A, mean tumor greatest dimension of 8.4 ± 3.7 cm, and lesion number of less than 4. The circulating immune cells and lymphocyte subtypes were quite heterogeneous among patients at baseline, e.g., the median percent of CD8+T cell was 27% (95% CI, 19% - 43%). The treatment induced changes of circulating immune components were heterogeneous from patient to patient but most significant after SBRT. On average, CD8+T cell (27% to 51%, p = 0.01) increased after sequential treatment, while its non-effector component CD127+CD8+T cell (51% to 18%, p < 0.001) decreased significantly. SBRT reduced the counts of lymphocyte (1.3 to 0.7, p < 0.001) and platelet (226 to 156, p=0.001), while T cell increased significantly (45% to 54%, p = 0.031). Our pilot study of 12 patients demonstrated 58.3% tumor control (7 complete response, 5 progression disease). After grouping by treatment response, the baseline CD4+T (65% vs. 53%, p = 0.01), Th1 cells (21% vs. 10%, p = 0.007) and Th1/Th17 (10% vs. 1%, p = 0.001) were significantly higher in responders, while CD25+CD8+T (4% vs. 12%, p < 0.001), CD127+CD8+T (42% vs. 60%, p = 0.003), Th17 (2% vs. 8%, p = 0.047) and Treg cells (p = 0.002) and ratio of Th2/Th1 (3% vs. 9%, p = 0.028) were significantly higher in non-responders. <h3>Conclusion</h3> This pilot study revealed heterogeneous components of systemic immunities at baseline and changes after different treatments, with most significant changes from SBRT. Future scale verification trials are warranted.