APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy

Driscoll, Christopher B.; Schuelke, Matthew; Kottke, Timothy; Thompson, Jill; Wongthida, Phonphimon; Tonne, Jason M.; Huff, Amanda L.; Miller, Amber C.; Shim, Kevin G.; Molan, Amy M.; Wetmore, Cynthia; Selby, Peter J.; Samson, Adel; Harrington, Kevin; Pandha, Hardev; Melcher, Alan; Pulido, José S.; Harris, Reuben S.; Evgin, Laura; Vile, Richard G.

doi:10.1038/s41467-020-14568-7

Cited by 52 publications

(73 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, clinical trials of immunotherapy in breast cancer show that tumors respond better when administered in earlier lines of therapy (reviewed by (20)). Given our findings, prior evidence in murine models (31,32), and human genomic studies implicating APOBEC mutagenesis in immune infiltration (60,64,65) and immunotherapy response (27)(28)(29)(30)67), . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

Section: Basalsupporting

confidence: 69%

“…In a recent study using mouse models of TNBC, overexpression of the murine APOBEC3 ortholog sensitized tumors to checkpoint inhibitors (31). Additionally, overexpression of human APOBEC3B in a vaccine setting sensitized mouse melanomas to checkpoint inhibition (32). However, the direct consequences of APOBEC mutagenesis on the tumor immune microenvironment and tumor growth in the absence of checkpoint inhibitors have not been thoroughly explored.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

APOBEC mutagenesis inhibits breast cancer growth through induction of a T cell-mediated antitumor immune response

DiMarco

Qin

Alsten

et al. 2021

Preprint

View full text Add to dashboard Cite

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 particularly enriched in the HER2 subtype of breast cancer and have been 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 induces 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. Consistent with the observed immune infiltration in APOBEC tumors, APOBEC activity sensitized HER2-driven breast tumors to checkpoint inhibition. 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 as a biomarker predicting immunotherapy response in HER2-positive breast cancers.

show abstract

Section: Basalsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

APOBEC mutagenesis inhibits breast cancer growth through induction of a T cell-mediated antitumor immune response

DiMarco

Qin

Alsten

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…However, the impact of the APOBEC-induced mutations depends on their number and at high levels can cause cell death by causing replication catastrophe or by inducing synthetically lethal mutations ( 91 ). Alternatively, high numbers of mutations can also induce neoepitopes that increase immune recognition ( 87 ). These effects of APOBECs are consistent with chemotherapeutic agents that try to induce such catastrophes in cells and may be the reason why APOBEC-induced mutations that are recovered from cancer genomes occur episodically ( 88 , 90 ).…”

Section: Discussionmentioning

confidence: 99%

APOBEC1 cytosine deaminase activity on single-stranded DNA is suppressed by replication protein A

Wong

Vizeacoumar

Chelico

2020

Nucleic Acids Research

View full text Add to dashboard Cite

Many APOBEC cytidine deaminase members are known to induce ‘off-target’ cytidine deaminations in 5′TC motifs in genomic DNA that contribute to cancer evolution. In this report, we characterized APOBEC1, which is a possible cancer related APOBEC since APOBEC1 mRNA is highly expressed in certain types of tumors, such as lung adenocarcinoma. We found a low level of APOBEC1-induced DNA damage, as measured by γH2AX foci, in genomic DNA of a lung cancer cell line that correlated to its inability to compete in vitro with replication protein A (RPA) for ssDNA. This suggests that RPA can act as a defense against off-target deamination for some APOBEC enzymes. Overall, the data support the model that the ability of an APOBEC to compete with RPA can better predict genomic damage than combined analysis of mRNA expression levels in tumors and analysis of mutation signatures.

show abstract

“…Nevertheless, APOBEC3B-mediated mutations could generate heteroclitic neoepitopes in vaccine cells that induced T cell responses de novo manner and this resulted in significant cures in subcutaneous and intracranial tumor models. These results suggested that an increased mutational load in tumor cell vaccines could enhance their immunogenicity to propel therapy for cancer which can be carried out in combination with immune checkpoint blockade [ 36 ]. Functional details of APOBEC2 and APOBEC4 are yet to be defined.…”

Section: Apobec: a Mutatormentioning

confidence: 99%

APOBEC: A molecular driver in cervical cancer pathogenesis

et al. 2021

View full text Add to dashboard Cite

Cervical cancer is one of the foremost common cancers in women. Human papillomavirus (HPV) infection remains a major risk factor of cervical cancer. In addition, numerous other genetic and epigenetic factors also are involved in the underlying pathogenesis of cervical cancer. Recently, it has been reported that apolipoprotein B mRNA editing enzyme catalytic polypeptide like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. Particularly, the APOBEC3 family was shown to induce tumor mutations by aberrant DNA editing mechanism. In general, APOBEC3 enzymes play a pivotal role in the deamination of cytidine to uridine in DNA and RNA to control diverse biological processes such as regulation of protein expression, innate immunity, and embryonic development. Innate antiviral activity of the APOBEC3 family members restrict retroviruses, endogenous retro-element, and DNA viruses including the HPV that is the leading risk factor for cervical cancer. This review briefly describes the pathogenesis of cervical cancer and discusses in detail the recent findings on the role of APOBEC in the molecular pathogenesis of cervical cancer.

show abstract

APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy

Cited by 52 publications

References 67 publications

APOBEC mutagenesis inhibits breast cancer growth through induction of a T cell-mediated antitumor immune response

APOBEC mutagenesis inhibits breast cancer growth through induction of a T cell-mediated antitumor immune response

APOBEC1 cytosine deaminase activity on single-stranded DNA is suppressed by replication protein A

APOBEC: A molecular driver in cervical cancer pathogenesis

Contact Info

Product

Resources

About