ISSN: 1837-9664Journal of Cancer
Global reach, higher impact
J Cancer 2024; 15(6):1687-1700. doi:10.7150/jca.92101 This issue Cite
Research Paper
An Investigation of the Immune Microenvironment and Genome during Lung Adenocarcinoma Development
1. Department of Pathology, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China.
2. Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078 China.
3. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China.
4. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, 410078, China.
5. Department of Pathology, The Second Xiangya Hospital, Central South University Changsha, Hunan, 410011, China.
Abstract
Background: Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are two consecutive pathological processes that occur before invasive lung adenocarcinoma (LUAD). However, our understanding of the immune editing patterns during the progression of LUAD remains limited. Furthermore, we know very little about whether alterations in driver genes are involved in forming the tumor microenvironment (TME). Therefore, it is necessary to elucidate the regulatory role of TME in LUAD development from multiple dimensions, including immune cell infiltration, molecular mutation events, and oncogenic signaling pathways.
Methods: We collected 145 surgically resected pulmonary nodule specimens, including 28 cases of AIS, 52 cases of MIA, and 65 cases of LUAD. Immunohistochemistry (IHC) was used to detect the expression of immune markers CD3, CD4, CD8, CD68 and programmed death ligand 1 (PD-L1). Genomic data and TMB generated by targeted next-generation sequencing (NGS).
Results: LUAD exhibited higher levels of immune cell infiltration, tumor mutation burden (TMB), and activation of oncogenic pathways compared to AIS and MIA. In LUAD, compared to epidermal growth factor receptor (EGFR) single mutation and wild-type (WT) samples, cases with EGFR co-mutations showed a more pronounced rise in the CD4/CD8 ratio and CD68 infiltration. Patients with low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B) mutation have higher TMB and PD-L1 expression. The transition from AIS to LUAD tends to shift the TME towards the PD-L1+CD8+ subtype (adaptive resistance). Progression-associated mutations (PAMs) were enriched in the lymphocyte differentiation pathway and related to exhausted cells' phenotype.
Conclusion: Tumor-infiltrating immune cells tend to accumulate as the depth of LUAD invasion increases, but subsequently develop into an immune exhaustion and immune escape state. Mutations in EGFR and LRP1B could potentially establish an immune niche that fosters tumor growth. PAMs in LUAD may accelerate disease progression by promoting T cell differentiation into an exhausted state.
Keywords: pre-invasive adenocarcinoma, immunoediting, tumor-infiltrating lymphocytes, tumor immune typing
Citation styles
