Invariant NK T cells counteract HCC metastasis by mediating the migration of splenic CD4+ T cells into the white pulp and infiltration of B cells.

Despite significant advances in the diagnosis and treatment of hepatocellular carcinoma (HCC), metastasis and recurrence remain two major obstacles to improving the clinical outcomes for HCC patients. Here, we demonstrate that splenic invariant natural killer T (iNKT) cells can significantly inhibit Hepa1-6-mediated intrahepatic HCC metastasis. Interestingly, in the HCC metastasis model, iNKT deficiency can result in a significant decrease in percentage and absolute number of CD4+ T cell and interleukin-4 level, thus suggesting the involvement of the cross-talk between iNKTs and CD4+ T cells in limiting HCC metastasis to the spleen. Transcriptional signatures of CD4+ T cells following iNKT deficiency displaying impairment of their cell migration function. During HCC metastasis, splenic iNKT rapidly secrete interferon-γ to promote the migration of CD4+ T cells from the marginal zone into the white pulp, thereby triggering subsequent migration of splenic B cells to the liver and exerting anti-tumor immune effects on Hepa1-6 cells. In conclusion, interactions between interferon-γ and its receptor on iNKT and CD4+ T cells can effectively coordinate immune activity between the marginal zone and the white pulp, thereby ultimately inhibiting intrahepatic HCC metastasis. These findings reveal the mechanism underlying the resistance of splenic iNKT to tumor metastasis.