In the present study, the characteristics of LUAD somatic mutations were studied in 538 samples from the United States and 507 samples from China. Next, we found that COL22A1 or DNAH8 mutation frequently occur in both ICGC and TCGA sample cohorts. Subsequently, COL22A1 or DNAH8 mutation was recognized to be related to higher TMB and poorer patient clinical results. Furthermore, in COL22A1 or DNAH8 mutation LUAD patients, signaling pathways about immune response were significantly abundant. Finally, COL22A1 or DNAH8 mutation LUAD samples emerge ed that the most infiltrating cells are Tregs, NK cells, B cells, and T cells. which is consistent with previous studied evidence that the anti-tumor immune reaction was related to these immune cells and immune pathways (17–20).
COL22A1 is a kind of micro collagen, which belongs to the family of fibronectin collagens with interrupted triple helices(21). Its biological function has been poorly understood. Firstly, Studies have shown that COL22A1, markers of early articular chondrocytes, is co-expressed with Lgr5 + cells before cavitation and serves as an important lineage marker indicating the progression to articular chondrocytes(22). In addition, in cancer, collagen is the main component of the extracellular matrix, which plays an important role in the occurrence and development of tumor. The upregulation of COL22A1 mRNA may play a key role in the progression of head and neck squamous cell carcinoma (HNSCC) and provide useful information for prognostic prediction of HNSCC patients(23). A network science date illustrated that COL22A1 was one of the four susceptibility genes prioritized by all described indicators as the most influential on colorectal cancer (CRC) among 512 top-ranked single-nucleotide polymorphisms(24). Finally, there were data suggested that mutations in COL22A1 could be one of the risk factors for intracranial aneurysms in humans(21). DNAH8, a protein coding gene, which is on chromosome 6q21.2, a cancer-associated amplicon(25), and is primarily expressed in prostate and testis(26). Its expression in primary tumor is higher than that in normal prostate, and it is further increased in metastatic prostate cancer (26). Although the role of DNAH8 has been poorly documented, phylogenetic sequence analysis suggested that DNAH8 is an axonemal dynein and likely an outer-arm axonemal dynein (data not shown)(26).In the present study, we revealed that COL22A1 or DNAH8 mutations indicated a poorer prognosis and were associated with increased TMB. In addition, TMB represents the mutation accumulation of somatic in tumors, high TMB helps to expose more new antigens, which is likely to cause T cell-dependent immune reaction(27). So that, we hypothesized that COL22A1 or DNAH8 mutations might promote anti-tumor immune response.
Recently, more and more studies have focused on the relationship between immune cell infiltration and cancer progression and prognosis. Human regulatory CD4 T cells (Tregs) are a subset of adaptive lymphocytes well characterized for their immunosuppressive functions and maintenance of immunological tolerance(28). Increased infiltration of Tregs is associated with poor prognosis in several kinds of cancer, including breast, lung, and kidney cancer (18, 29, 30). In our research, we also found that LUAD samples with COL22A1 mutation had higher Tregs loads, which means a poor prognosis that in line with our results. In addition, we observed that DNAH8 mutation was associated with increased B cells infiltrations. B cells are recognized as the main effector cells of humoral immunity which suppress tumor progression by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly(31). Upon entering the local microenvironment, tumor antigens released from lung cancer cells aid in B cell aggregation and trigger B cell-mediated antigen presentation, which facilitate the maintenance of B cell activation and proliferation(32). In addition, a higher percentage of follicular helper T cells were uncovered in COL22A1 or DNAH8 mutant group. Daniel et al. revealed that immunocheckpoint therapy induces activation of t-follicular helper cells of B cells to promote anti-tumor response in mouse models of triple-negative breast cancer. Therefore, our results suggested that COL22A1 mutation induced the altered of tumor infiltration immune cells can help the patients with LUAD anti-tumor immunity and DNAH8 mutation induced the altered of tumor infiltration immune cells can suppress the patients with LUAD anti-tumor immunity.
There are some limitations in this study. In the absence of clinical data from ICGC database samples, we were unable to determine if COL22A1 or DNAH8 mutations are also related to tumor immunity and prognosis in the patients with LUAD in China. Moreover, tumor immunotherapy is a very complex topic, including immune cells, cytokines, immune microenvironment, tumor-related gene mutations and antigens, Etc; while this study is all informatics analyses and further experimental validations are needed.