Overcoming Immunotherapy Resistance in Tumors: Targeting Treg Recruitment through CCR4 Regulation

The abstract discusses the role of checkpoint inhibitors (CPIs) in cancer treatment and the challenges of resistance. It highlights the role of regulatory T cells (Treg) in resistance and their migration to tumors, which is mediated by the CC chemokine receptor 4 (CCR4). The study presents the development of a CCR4 antagonist, CCR4-351, to assess its impact on Treg migration and antitumor efficacy. Two mouse tumor models were used to evaluate the effects of the antagonist alone or in combination with CPIs.

The results indicate that the CCR4 inhibitor effectively reduces the migration of Treg into the tumor, leading to enhanced antitumor immune responses. In tumors with high baseline CCR4 ligand levels, CCR4 blockade decreased Treg numbers and improved immune activity. Interestingly, CPI treatment in tumors with low baseline CCR4 ligand levels led to an increase in these ligands and Treg numbers, which were reduced by CCR4 inhibition, thereby enhancing the CPIs' antitumor effects.

The conclusion emphasizes that CCR4-dependent Treg recruitment is a significant factor in immune resistance to cancer. The study supports the potential of combining CCR4 inhibitors with CPIs for cancer treatment, as it shows that blocking CCR4 can reduce Treg frequency and increase antitumor activity.

Lastly, the significance statement points out that CPIs can increase the expression of CCL17 and CCL22 in tumors, promoting Treg migration. The pharmacological targeting of the CCR4 receptor can effectively inhibit this migration and improve the antitumor efficacy of treatments, either as a standalone therapy in tumors with high CCR4 ligand expression or in combination with CPIs for tumors with low expression.