WNT pathway inhibition sensitizes HAT1-high lung cancers to treatment with PD-1 inhibitors.

backgroundImmunotherapies change the paradigm of current pulmonary oncological clinics, although majority of patients fail to benefit from these treatment modalities. HAT1 overexpression is frequently diagnosed in lung cancer patients. Effective immunotherapeutic scheme remains to be determined for this portion of patients.

methodsIn vitro experiments were used to verify the transcriptional regulation of PD-L1 by HAT1 in lung cancer cells. Mouse syngeneic lung tumors with sgHAT1 were treated with PD-1 antibodies to determine the impact of deficiency of HAT1 on the sensitivity of lung cancers to PD-1 inhibitors. RNA-seq and Chip-seq analyses revealed the effect of HAT1 on the WNT pathway. The impact of HAT1 on WNT signaling on stemness of lung cancer cells and their ability to escape immune surveillance were evaluated through a series of in vitro and in vivo experiments. Clinical relevance of expression level of HAT1 on prognosis of lung cancer patients were assessed using data from multiple public datasets. Carcinogenicity of HAT1 was evaluated using a transgenic mouse model in vivo.

resultsSilencing HAT1 expression downregulated PD-L1 expression in murine and human lung cancer cells. Notably, HAT1-knockout sensitized lung cancers to PD-1 antibody treatment. We found that HAT1 enhanced the stemness of lung cancer cells through enhancing expression of WNT ligands by direct binding of their promoter regions. WNT pathway inhibitor, ICG001, sensitized lung tumors to treatment with PD-1 antibody. HAT1 overexpression was highly frequent among lung cancer patients and was found transforming in vitro and tumorigenic in vivo.

conclusionThis study demonstrates that overexpression HAT1 plays a critical role in mediating immune evasion in lung cancer. Mechanistically, on one hand, HAT1 upregulate PD-L1 expression in lung cancer cells. On the other hand, HAT1 enhances stem-like properties of lung cancer cells by upregulating several WNT ligands. Consequently, combined inhibition of the WNT pathway and PD-1 signaling effectively shrinks HAT1-high lung cancers. These findings highlight the critical role of HAT1 overexpression in lung cancer development and shed light on potential precision medicine for this portion of lung cancer patients.