p62/SQSTM1 impairs immunotherapy in lung adenocarcinoma by suppressing immune infiltration and peripheral immune response

Purpose: We aim to find a potential immunotherapeutic target for lung adenocarcinoma (LUAD) patients. Methods: We collected 193 normal and 543 LUAD tumor samples in total from GEO database. ESTIMATE algorithm, limma and ssGSEA methods were used to find immune-related differential expression genes and to quantify the immune infiltration levels. Preclinical experiments were performed to confirm the role of p62 on LUAD cell lines. And retrospective cohort analyses were used to discover the relationship between p62 and LUAD patients’ peripheral immune status, tumor immune infiltration levels and prognosis of immunotherapy. Results: We confirmed that p62 was overexpressed in LUAD patients whose expression corresponded with lower survival. Simultaneously, we discovered an association of p62 with immune cells, wherein high p62 expression in LUAD patients corresponded with fewer tumor-infiltrating lymphocytes, again associated with a poorer prognosis. We revealed that p62 significantly promoted cell proliferation, migration, invasion, and epithelial-mesenchymal transition in vitro. Moreover, we found that p62 somatic copy number alterations corresponded with tumor infiltration of immune cells. In addition, both expression and methylation level of p62 were significantly correlated with immune cell infiltration. Importantly, we demonstrated in a small cohort of LUAD patients receiving immune checkpoint inhibitors (ICIs) that p62 levels were negatively associated with lower levels of circulating and infiltrated lymphocytes and shorter progression-free survival of ICI treatment. Conclusion: We demonstrated the involvement of p62 in immune cell infiltration and peripheral immune cell status in LUAD, as well as preliminarily characterized its roles in cancer progression, thus identifying a potential prediction and prognostic marker for LUAD immunotherapy.