APOBEC Mutagenesis Inhibits Breast Cancer Growth through Induction of T cell–Mediated Antitumor Immune Responses

Abstract

The APOBEC family of cytidine deaminases is one of the most common endogenous sources of mutations in human cancer. Genomic studies of tumors have found that APOBEC mutational signatures are enriched in the HER2 subtype of breast cancer and are associated with immunotherapy response in diverse cancer types. However, the direct consequences of APOBEC mutagenesis on the tumor immune microenvironment have not been thoroughly investigated. To address this, we developed syngeneic murine mammary tumor models with inducible expression of APOBEC3B. We found that APOBEC activity induced antitumor adaptive immune responses and CD4+ T cell–mediated, antigen-specific tumor growth inhibition. Although polyclonal APOBEC tumors had a moderate growth defect, clonal APOBEC tumors were almost completely rejected, suggesting that APOBEC-mediated genetic heterogeneity limits antitumor adaptive immune responses. Consistent with the observed immune infiltration in APOBEC tumors, APOBEC activity sensitized HER2-driven breast tumors to anti–CTLA-4 checkpoint inhibition and led to a complete response to combination anti–CTLA-4 and anti-HER2 therapy. In human breast cancers, the relationship between APOBEC mutagenesis and immunogenicity varied by breast cancer subtype and the frequency of subclonal mutations. This work provides a mechanistic basis for the sensitivity of APOBEC tumors to checkpoint inhibitors and suggests a rationale for using APOBEC mutational signatures and clonality as biomarkers predicting immunotherapy response in HER2-positive (HER2+) breast cancers.

APOBEC-mediated mutagenesis is a favorable predictor of prognosis and immunotherapy for bladder cancer patients: evidence from pan-cancer analysis and multiple databases

“…However, the role of APOBECs in cancers remains ambiguous. For example, it is reported that APOBEC mutagenesis could drive tumor evolution in metastatic thoracic tumor and HPV-driven tumor but inhibit breast cancer growth through immune activation 12 , 53 , 54 . When it comes to APOBEC3B, it is the most widely investigated member of APOBEC family and causes a variety of mutagenic outcomes 55 , but its biological impact on cancers still remains unclear, even contrary.…”

Pan-Cancer Analysis for Immune Cell Infiltration and Mutational Signatures Using Non-Negative Canonical Correlation Analysis

“…As mentioned above, the relationships between the mutational signatures and immunity were studied in LUSC [11,12], which showed that the APOBEC signature was associated with the immune response. Furthermore, recently, the relationship between APOBEC mutagenesis and the immune response in breast cancer has been reported [50], and some studies have shown an association between APOBEC mutagenesis and immunity in HNSC [51,52]. In my experimental results, the APOBEC signatures were also observed as the highest coefficients in BRCA, HNSC, as well as LUSC.…”

Epigenetics and environment in breast cancer: New paradigms for anti-cancer therapies

“…Furthermore, while, APOBEC1 possesses DNA demethylase activity ( 48 – 50 ), APOBEC mutagenesis influencing the tumor evolution in ER+/HER2-breast cancer has been reported ( 51 ). Most recently it was shown that the APOBEC mutagenesis prohibited the growth of breast tumors by eliciting immunogenic responses ( 52 ).…”