Identification of upstream immunoregulators that target protein co-expression networks significantly associated with early-stage micropapillary/solid predominant lung adenocarcinomas

Abstract Micropapillary- and solid-predominant lung adenocarcinomas (MPA and SPA), high-risk subtypes with poor outcomes, remain their molecular profiles unclarified. This study aimed at identifying the disease-related protein networks associated with early-stage MPA and SPA. We assessed cancerous cells laser-microdissected from FFPE tissues of an MPA group (n = 3) and a SPA group (n = 5), referencing the lepidic predominant subtype group (LPA) (n = 4). We identified forty modules of protein co-expression networks by applying a weighted network correlation analysis to the quantitative proteome datasets. Upstream analysis was then applied to four modules significantly associated with MPA or SPA. The redox master regulator NFE2L2 was activated commonly in both MPA and SPA cases. The two MPA-significant modules suggested p53 inactivation by dual mechanisms. One involves NGFR (p75NTR) and another the highly expressed myoferlin (MYOF), potentially induced by the ASPSCR1-TFE3 oncoprotein. The two SPA-significant modules commonly predicted the highly inhibited LARP1, indicating oncogenic IRES-dependent translation. Moreover, together with our observation of the highly expressed immune checkpoint molecules HLA-G and IDO1, activated regulators of adaptive immune response and inhibition of LILRB2 implicated that early-stage SPA is already associated with anti-tumor immune tolerance. Our findings might help develop future therapeutic strategies.