Survival impact of immune cells infiltrating peritumoral area of hepatocellular carcinoma

• Published in: Cancer science 2022-12, Vol.113 (12), p.4048-4058
• Main Authors: Yusa, Toshihiko, Yamashita, Yo‐ichi, Okabe, Hirohisa, Nakao, Yosuke, Itoyama, Rumi, Kitano, Yuki, Kaida, Takayoshi, Miyata, Tatsunori, Mima, Kosuke, Imai, Katsunori, Hayashi, Hiromitsu, Baba, Hideo
• Format: Article
• Language: English
• Subjects: Antibodies; Antigens; Carcinoma, Hepatocellular - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes; Hepatectomy; Hepatitis B; Hepatitis C; Hepatocellular carcinoma; Humans; immune cell; Immunohistochemistry; Immunoregulation; Inflammation; Leukocytes (neutrophilic); Liver cancer; Liver Neoplasms - metabolism; Lymphocytes; Lymphocytes T; Macrophages; Medical prognosis; Medical research; Metastases; Neutrophils; Original; ORIGINAL ARTICLES; Patients; Prognosis; Software; Surgery; T-Lymphocytes, Regulatory; Tumor Microenvironment; Tumors; tumor‐associated neutrophil
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15437

Inflammatory and immune cells in the tumor microenvironment are reported to be associated with tumor progression in several cancers. In total, 225 patients who underwent initial and curative hepatectomy for hepatocellular carcinoma (HCC) from 2004 to 2013 were enrolled in this study. Tumor‐associated neutrophils (TANs), M2 macrophages (TAMs; tumor‐associated macrophages), CD8+ T cells, and regulatory T cells (Tregs) were evaluated by immunohistochemistry (IHC), and their relationships with patient clinicopathological characteristics and prognosis were evaluated. IHC was performed focusing on TANs first. We could not find a relationship between intratumoral and peritumoral TANs and clinicopathological features except for the fibrous capsule and infiltration of tumors into capsule. Next, TAMs, CD8+ cells and Tregs were evaluated by IHC. At the peritumoral area, TANs and TAMs (r = 0.36, p = 0.001) or Tregs (r = 0.16, p = 0.008) showed a positive correlation, whereas TANs and CD8+ cells showed a negative correlation (r = −0.16, p = 0.02). As for survival outcomes, at the peritumoral area, high TANs (p = 0.0398), low CD8+ cells (p = 0.0275), and high TAMs (p = 0.001) were significantly associated with worse overall survival (OS). In addition, high TANs (p = 0.010), and high TAMs (p = 0.00125) were significantly associated with worse disease‐free survival (DFS). Finally, we established a risk signature model by combining the expression patterns of these cells. The high‐risk signature group had significantly worse OS (p = 0.0277) and DFS (p = 0.0219) compared with those in the low‐risk signature group. Our risk signature based on immune cells at the peritumoral area of the HCC can predict patient prognosis of HCC after curative hepatectomy. In this study, we showed that infiltration of inflammatory and immune cells at peri‐tumoral site of HCC showed a significant association with patients’ prognosis. We also made risk signature evaluated by the infiltration of immune cells at peri‐tumoral site of HCC, and it might to be a new prognostic marker of patients with HCC after curative hepatectomy.