Enhanced formation of tertiary lymphoid structures shapes the anti-tumor microenvironment in hepatocellular carcinoma after FOLFOX-HAIC therapy
Rui Xing, Jie Mei, Zhijun Zuo, Hao Zou, Xing-Juan Yu, Jing Xu, Rong Guo, Wei Wei, Limin Zheng
Abstract
Tertiary lymphoid structures (TLSs) emerge as crucial determinants of anti-tumor immune responses and clinical outcomes. However, their clinical significance and formation mechanisms in hepatocellular carcinoma (HCC) remain unclear. Here, we demonstrate that hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and fluorouracil (FOLFOX) significantly enhances TLS formation in HCC tissues, correlating with improved therapeutic efficacy and prolonged progression-free survival in patients with HCC. Mechanistically, HAIC induces lymphotoxin β (LTβ)-expressing central memory T cell (T CM )-like CD4 + T cells, which activate MMP2 + fibroblasts and FOLR2 + CCL4 + macrophages via the LTβ-LTβR axis to drive TLS development. Furthermore, the CXCL12-CXCR4 axis acts as a critical mediator in recruiting these cells to HAIC-treated tumors, thereby facilitating TLS formation and enhancing anti-tumor immunity. These findings highlight the pivotal role of TLSs in HAIC-induced anti-tumor immunity and their significance as robust prognostic biomarkers, offering potential therapeutic targets to optimize clinical outcomes for patients with HCC. • Intra-tumor TLSs predict better response and prognosis in HAIC-treated patients with HCC • T CM -like CD4 + T cells, fibroblasts, and macrophages cooperate to induce TLS formation • The CXCL12-CXCR4 axis plays a key chemotactic role in intra-tumor TLS development Xing et al. reveal that HAIC promotes TLS formation in HCC, enhancing anti-tumor immunity and patient outcomes. TLS development is orchestrated by CD4 + T cells, fibroblasts, and macrophages via the LTβ-LTβR and CXCL12-CXCR4 axes, highlighting TLS as a prognostic biomarker and a therapeutic target to enhance HAIC efficacy in HCC.