APOBEC3G Expression Correlates with T-Cell Infiltration and Improved Clinical Outcomes in High-grade Serous Ovarian Carcinoma

Abstract

Purpose APOBEC3 DNA cytosine deaminase family members normally defend against viruses and transposons. However, deregulated APOBEC3 activity causes mutations in cancer. Due to broad expression profiles and varying mixtures of normal and cancer cells in tumors, including immune cell infiltration, it is difficult to determine where different APOBEC3s are expressed. Here, we ask whether correlations exist between APOBEC3 expression and T cell infiltration in high-grade serous ovarian cancer (HGSOC), and assess whether these correlations have prognostic value. Experimental Design Transcripts for APOBEC3G, APOBEC3B, and the T cell markers, CD3D, CD4, CD8A, GZMB, PRF1, and RNF128 were quantified by RT-qPCR for a cohort of 354 HGSOC patients. Expression values were correlated with each other and clinical parameters. Two additional cohorts were used to extend HGSOC clinical results. Immuno-imaging was used to colocalize APOBEC3G and the T cell marker CD3. TCGA data extended expression analyses to additional cancer types. Results A surprising positive correlation was found for expression of APOBEC3G and several T cell genes in HGSOC. Immunohistochemistry and immunofluorescent imaging showed protein colocalization in tumor-infiltrating T lymphocytes. High APOBEC3G expression correlated with improved outcomes in multiple HGSOC cohorts. TCGA data analyses revealed that expression of APOBEC3D and APOBEC3H also correlates with CD3D across multiple cancer types. Conclusions Our results identify APOBEC3G as a new candidate biomarker for tumor-infiltrating T lymphocytes and favorable prognoses for HGSOC. Our data also highlight the complexity of the tumor environment with respect to differential APOBEC family gene expression in both tumor and surrounding normal cell types.

APOBEC3G is increasingly expressed on the human uterine cervical intraepithelial neoplasia along with disease progression

“…In the CIN lesions, we observed A3G‐positive cells, which had a round nucleus and narrow rim of cytoplasm, infiltrating the epithelial and subepithelial stromal regions (Figure E). These A3G‐positive cells were positive for CD3, a cell marker of T lymphocytes, in accordance with previous reports in ovarian cancer (data not shown). The numbers of A3G‐positive cells infiltrating around CIN3 lesions were significantly higher than those of CIN1 and CIN2 lesions (Figure ).…”

“…In this study, we observed that a large number of A3G‐positive immune cells had infiltrated around the CIN lesions. Based on our preliminary study using a double‐fluorescent staining method, these cells also expressed CD3, as was reported in the case of ovarian cancers . Importantly, the number of the A3G‐positive T cells increased according to the grade of the CIN lesions, suggesting that these immune cells are involved in the pathological course of HPV‐induced CIN lesions.…”

Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation

“…As a side note, increased expression of A3D and A3H was associated with a better overall survival (OS) in this study, which seems paradoxical, or at least cannot be explained yet. Thus, further investigations concerning APOBEC expression patterns and response to checkpoint inhibitors are warranted.In high grade serous ovarian carcinomas APOBEC3 expression was significantly associated with T-cell infiltration and -seemingly paradoxically- with improved clinical outcome [69]. …”

“…In high grade serous ovarian carcinomas APOBEC3 expression was significantly associated with T-cell infiltration and -seemingly paradoxically- with improved clinical outcome [69]. …”

Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC

“…We therefore resorted to a re-analysis of publicly available single cell gene expression data. Doing so, we were able to circumvent the bias of measuring APOBEC3 activity in the tumor microenvironment (Leonard et al, 2016).…”