2313P - APOBEC mutagenesis and macrophage infiltration in cancer

Background

APOBEC enzymes play key roles in DNA editing and are highly expressed in various cancer types, including estrogen receptor (ER)+/HER2- breast cancer (BC). APOBEC enzyme activation promotes mutagenesis that results in the generation of neoantigens, potentially leading to an anti-tumor immune response. APOBEC mutagenesis has been associated to resistance to chemotherapy and immunotherapy. The impact of APOBEC mutagenesis on the tumor microenvironment (TME) still remains unclear. Here we sought to characterize the TME of ER+/HER2- BC displaying APOBEC mutagenesis and to validate the findings in other APOBEC-related cancer types.

Methods

ER+/HER2- BCs from TCGA with available whole exome and RNA-sequencing data were included (n=519). We inferred single base substitutions (SBS) mutational signatures using SigProfiler. Cell type fractions were computed using CIBERSORT. The correlation between APOBEC signatures (SBS signatures 2 and 13) and the abundance of TME cell types was defined using a logistic regression model adjusted by tumor mutation burden. False discovery rate correction was applied (q-value). Other APOBEC-related cancers (bladder, head and neck, cervix and uterine) were assessed.

Results

Of 519 ER+/HER2- BCs, 57 (11%) were classified as APOBEC-dominant, 84 (16%) as non-dominant-APOBEC and the remaining 378 (73%) as non-APOBEC. Compared to non-APOBEC, APOBEC-dominant ER+/HER2- BCs displayed an enrichment for macrophages M1 infiltration (q=0.026), and decreased macrophage M2 population (q=0.017). Non-dominant APOBEC BCs displayed an extent of macrophage M1 and M2 infiltration intermediate between the other two groups. Analysis of the TME composition according to APOBEC mutagenesis in bladder (n=389), head and neck (n=463), cervical (n=269) and uterine (n=474) cancers revealed differences comparable to those observed in ER+/HER2- BCs.

Conclusions

An association between APOBEC mutagenesis and macrophages M1 infiltration was observed, suggesting that APOBEC processes may uniquely shape the TME in cancer. Going forward, we will investigate the impact of other mutagenesis processes, such as homologous recombination deficiency (HRD), on the TME, to gain a comprehensive understanding of the interplay between various mutational processes and the TME.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Breast cancer research foundation and National Institutes of Health/National Cancer Institute.

Disclosure

B. Weigelt: Financial Interests, Institutional, Research Funding: Repare Therapeutics. J.S. Reis-Filho: Financial Interests, Personal, Other, Consultant: Goldman Sachs, Eli Lilly, Saga Diagnostics; Financial Interests, Personal, Other, Member of the Scientific Advisory Board and Consultant: Repare Therapeutics, Paige.AI; Financial Interests, Personal, Advisory Board: Personalis, Roche Tissue Diagnostics; Financial Interests, Personal, Advisory Board, Member of the Scientific Advisory Board: Bain Capital; Financial Interests, Personal, Advisory Board, Ad hoc member of the Pathology Scientific Advisory Board: Daiichi Sankyo, Merck; Financial Interests, Personal, Advisory Board, Ad hoc member of the Oncology Scientific Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board, Member of the SAB: MultiplexDX; Financial Interests, Personal, Member of Board of Directors: Odyssey Bio, Grupo Oncoclinicas; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics; Financial Interests, Personal, Other, Stock options: Paige.AI. S. Chandarlapaty: Financial Interests, Personal, Other, Consultant: Novartis, Boxer Capital, Nuvalent, Inivata, Neogenomics; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Personal and Institutional, Research Grant, Consultant: AstraZeneca; Financial Interests, Personal, Officer, Officer and Shares: Odyssey Biosciences; Financial Interests, Personal, Stocks/Shares: Totus Medicines. All other authors have declared no conflicts of interest.