# Anti-CTLA-4 treatment suppresses hepatocellular carcinoma growth through Th1-mediated cell cycle arrest and apoptosis

## TL;DR

This study shows that anti-CTLA-4 treatment fights liver cancer by activating Th1 cells, which cause cancer cell arrest and death.

## Contribution

The study reveals a novel mechanism where Th1 cells mediate anti-tumor effects of anti-CTLA-4 treatment in hepatocellular carcinoma.

## Key findings

- CD4+ T cells, not CD8+ T cells, are essential for anti-CTLA-4 Ab's anti-tumor effects.
- IFN-g-producing Th1 cells are recruited to tumors and are necessary for tumor suppression.
- IFN-g induces cell cycle arrest and apoptosis in cancer cells independently of MHC expression.

## Abstract

Inhibiting the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4)-mediated immune checkpoint system using an anti-CTLA-4 antibody (Ab) can suppress the growth of various cancers, but the detailed mechanisms are unclear. In this study, we established a monoclonal hepatocellular carcinoma cell line (Hepa1-6 #12) and analyzed the mechanisms associated with anti-CTLA-4 Ab treatment. Depletion of CD4+ T cells, but not CD8+ T cells, prevented anti-CTLA-4 Ab-mediated anti-tumor effects, suggesting dependence on CD4+ T cells. Anti-CTLA-4 Ab treatment resulted in recruitment of interferon-gamma (IFN-g)-producing CD4+ T cells, called T-helper 1 (Th1), into tumors, and neutralization of IFN-g abrogated the anti-tumor effects. Moreover, tumor growth suppression did not require major histocompatibility complex (MHC)-I or MHC-II expression on cancer cells. In vitro studies showed that IFN-g can induce cell cycle arrest and apoptosis in tumor cells. Taken together, these data demonstrate that anti-CTLA-4 Ab can exert its anti-tumor effects through Th1-mediated cell cycle arrest and apoptosis.