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<p>The APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family
of cytidine deaminases is one of the most common endogenous sources of single base
substitution mutations in human cancer. Accordingly, APOBEC enzymes represent a major
source of intratumor genetic heterogeneity and have been associated with immunotherapy
response in diverse cancer types. However, the consequences of APOBEC mutagenesis
on tumor progression in vivo are not well understood. To address this, I developed
several murine tumor models with inducible APOBEC3B expression and studied the contribution
of APOBEC activity to tumor evolution and immunogenicity. First, I explored the effects
of APOBEC activity on tumor relapse using a murine model of mammary tumor recurrence.
APOBEC activity led to a significant acceleration in tumor recurrence following the
strong selective pressure of oncogenic driver signaling loss. Recurrent APOBEC tumors
had undifferentiated histological features and large, irregularly shaped nuclei containing
defects like micronuclei, multinucleation, and chromatin bridges. I found that recurrent
APOBEC tumors amplified the therapy resistance-associated oncogene, c-Met, on circular
extrachromosomal DNA, likely driving the proliferation of the recurrent cancer cells.
Second, because APOBEC mutational signatures are enriched in the majority of HER2-positive
breast cancer patients, I used a syngeneic HER2-driven mammary tumor model to study
the effects of APOBEC activity on the tumor immune microenvironment. I found that
APOBEC activity induced an antitumor adaptive immune response and CD4+ T cell-mediated
tumor growth inhibition. While polyclonal APOBEC tumors had a moderate growth defect,
clonal APOBEC tumors were almost completely rejected by the immune system, suggesting
that APOBEC-mediated genetic heterogeneity limits the antitumor adaptive immune response.
In human breast cancers, the relationship between APOBEC mutagenesis and immunogenicity
varied by breast cancer subtype and the frequency of subclonal mutations. Consistent
with the observed immune infiltration in murine APOBEC tumors, APOBEC activity sensitized
HER2-driven breast tumors to checkpoint inhibition. 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 breast cancers.
In conclusion, I’ve identified a novel role for APOBEC activity in generating chromosomal
instability, consisting of mitotic errors, oncogene amplification, and extrachromosomal
DNA formation to promote tumor recurrence. Moreover, APOBEC activity also stimulated
an antitumor adaptive immune response and sensitized tumors to immunotherapy.</p>
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