Kurebayashi Yutaka, Sugimoto Katsutoshi, Tsujikawa Hanako, Matsuda Kosuke, Nomura Rui, Ueno Akihisa, Masugi Yohei, Yamazaki Ken, Effendi Kathryn, Takeuchi Hirohito, Itoi Takao, Hasegawa Yasushi, Abe Yuta, Kitago Minoru, Ojima Hidenori, Sakamoto Michiie
Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan.
Clin Cancer Res. 2024 Dec 16;30(24):5666-5680. doi: 10.1158/1078-0432.CCR-24-0479.
Immunotherapies have led to a paradigm shift in the treatment of hepatocellular carcinoma (HCC). Studies have revealed the single-cell catalogs of tumor-infiltrating immune cells and the trajectories of their differentiation. Nevertheless, the spatial distribution of these immune cells with distinct phenotypes in the tumor microenvironment and their clinicopathologic significance in resectable and unresectable HCCs are still largely unclear.
We analyzed the spatial dynamics of intratumoral CD4 and CD8 T cells and their association with B and plasma cells using 283 surgically resected HCC samples, 58 unresectable HCC samples before combined immunotherapy [atezolizumab plus bevacizumab (Atezo + Bev)], and autopsy specimens from 50 cases of advanced-stage HCC through multiplex IHC combined with transcriptomic and driver gene mutation analyses. Classification based on the spatial dynamics of T- and B-cell responses (refined immunosubtype) was developed, and its clinicopathologic significance was analyzed.
We found that stem-like CD4 and CD8 T cells were mainly observed in T-cell aggregates and T-cell zone of tertiary lymphoid structure (TLS). The differentiation of T follicular helper cells was associated with the development of TLS, whereas the differentiation of CXCL13-expressing CD4 TCXCL13 cells with a phenotype resembling T peripheral helper cells was associated with the development of the lymphoplasmacytic microenvironment. The refined immunosubtype could predict clinical outcomes of resectable HCC after surgery and unresectable HCC after Atezo + Bev therapy. The immune microenvironment of metastatic lesions tended to reflect those of primary lesions.
We revealed the spatial dynamics of T- and B-cell responses in HCC, which is closely associated with the clinical outcome after surgical resection or Atezo + Bev therapy.
免疫疗法已使肝细胞癌（HCC）的治疗发生了范式转变。研究揭示了肿瘤浸润免疫细胞的单细胞图谱及其分化轨迹。然而，这些具有不同表型的免疫细胞在肿瘤微环境中的空间分布及其在可切除和不可切除HCC中的临床病理意义仍 largely unclear。
我们使用283例手术切除的HCC样本、58例联合免疫治疗[阿替利珠单抗加贝伐单抗（阿替利珠单抗 + 贝伐单抗）]前的不可切除HCC样本以及50例晚期HCC的尸检标本，通过多重免疫组化结合转录组学和驱动基因突变分析，分析了肿瘤内CD4和CD8 T细胞的空间动态及其与B细胞和浆细胞的关联。基于T细胞和B细胞反应的空间动态（精细免疫亚型）进行了分类，并分析了其临床病理意义。
我们发现，干细胞样CD4和CD8 T细胞主要见于三级淋巴结构（TLS）的T细胞聚集区和T细胞区。T滤泡辅助细胞的分化与TLS的发育相关，而具有类似于T外周辅助细胞表型的CXCL13表达CD4 TCXCL13细胞的分化与淋巴浆细胞微环境的发育相关。精细免疫亚型可以预测可切除HCC术后以及阿替利珠单抗 + 贝伐单抗治疗后不可切除HCC的临床结局。转移灶的免疫微环境倾向于反映原发灶的免疫微环境。
我们揭示了HCC中T细胞和B细胞反应的空间动态，这与手术切除或阿替利珠单抗 + 贝伐单抗治疗后的临床结局密切相关。
