APOBEC Alteration Contributes to Tumor Growth and Immune Escape in Pan-Cancer

Abstract

The accumulating evidence demonstrates that the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. In particular, the APOBEC3 family was shown to induce tumor mutations by an aberrant DNA editing mechanism. However, knowledge regarding the reconstitution of the APOBEC family genes across cancer types is still lacking. Here, we systematically analyzed the molecular alterations, immuno-oncological features, and clinical relevance of the APOBEC family in pan-cancer. We found that APOBEC genes were widely and significantly differentially expressed between normal and cancer samples in 16 cancer types, and that their expression levels are significantly correlated with the prognostic value in 17 cancer types. Moreover, two patterns of APOBEC-mediated stratification with distinct immune characteristics were identified in different cancer types, respectively. In ACC, for example, the first pattern of APOBEC-mediated stratification was closely correlated with the phenotype of immune activation, which was characterized by a high immune score, increased infiltration of CD8 T cells, and higher survival. The other pattern of APOBEC-mediated stratification was closely correlated with the low-infiltration immune phenotype, which was characterized by a low immune score, lack of effective immune infiltration, and poorer survival. Further, we found the APOBEC-mediated pattern with low-infiltration immune was also highly associated with the advanced tumor subtype and the CIMP-high tumor subtype (CpG island hypermethylation). Patients with the APOBEC-mediated pattern with immune activation were more likely to have therapeutic advantages in ICB (immunological checkpoint blockade) treatment. Overall, our results provide a valuable resource that will be useful in guiding oncologic and therapeutic analyses of the role of APOBEC family in cancer.

Progress on neoadjuvant immunotherapy in resectable non-small cell lung cancer and potential biomarkers

“…Studies revealed other molecular markers that could be predictive of the efficacy of immunotherapy in advanced NSCLC. For example, detected through next-generation sequencing, the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like, also known as APOBEC, has been reported to predict the efficacy of immunotherapy ( 70 ), not only in NSCLC but also in pan-cancer analysis ( 71 ). Previous study ( 72 ) found that APOBEC signature in metastatic NSCLC is strongly associated with better immune responses, in terms of ORR and PFS.…”

APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential

“…APOBEC3s can also impact tumor growth through non-mutagenic pathways that shape the tumor immune microenvironment (Table 4 ). APOBEC3s are immunosuppressive in some cancers, and higher APOBEC3B expression has been associated with less immune cell infiltration in adrenocortical carcinoma and gastric cancer [ 37 , 162 ]. APOBEC3 expression has also been associated with greater infiltration of immunosuppressive mediators such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in a mouse model of hepatocellular carcinoma [ 163 ].…”

“…Fewer MDSCs and naïve CD4+ T cells Patient [ 160 ] 3B Activating More cytotoxic T-cells with a higher CD8+/CD3+ ratio Patient [ 35 ] Glioma 3B, 3C, 3D, 3F, 3G, 3H Activating Increased myeloid cell infiltration, IFN-γ signaling, and PD-L1/2 expression Patient [ 51 ] Lung 3B Activating More activated CD4+ T cells, CD8+ T cells, and NK cells. Fewer regulatory T cells Patient [ 166 ] 3B Activating Upregulation of immune genes and more T cell infiltration to the tumor site Patient [ 36 ] Mutation burden Activating Enrichment of interferon pathways Patient [ 89 ] Melanoma 3B Activating Immune activation in a multi-cancer analysis Patient [ 162 ] Ovarian 3B Activating Greater tumor immune cell infiltration Patient [ 41 ] 3G Activating Higher immune cell counts in the tumor microenvironment Patient [ 167 ...…”

“…The opposite effect has been observed in other cancer types, with APOBEC3s promoting immune activation. In a pan-cancer analysis, high APOBEC3B expression was associated with increased immune activation in cutaneous melanoma and breast cancer [ 162 ]. Additional studies in breast cancer have found similar results.…”

The coevolution between APOBEC3 and retrotransposons in primates

“…This activity leaves signatures along the double helix that are clearly traceable to A3 family members and are found predominantly in cancer cells [73]. As the structural details of A3s interaction with nucleic acids are being unveiled [74], the ambivalent effect of these protective enzymes is also being highlighted, as an elevated expression of APOBEC3s may provide a reason for aberrant cancer-inducing somatic mutations in human papilloma virus (HPV) [75][76][77] and HBV [78] infections, as well as an extensive range of other tumor types [73,79,80], even in the context of inflammation [81].…”