Abstract

The use of immune checkpoint blockade (ICB) using antibodies against programmed death receptor (PD)-1, PD ligand (PD-L)-1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has redefined the therapeutic landscape in solid tumors, including skin, lung, bladder, liver, renal, and breast tumors. However, overall response rates to ICB therapy remain limited in PD-L1-negative patients. Thus, rational and effective combination therapies will be needed to address ICB treatment resistance in these patients, as well as in PD-L1-positive patients who have progressed under ICB treatment. DNA damage repair inhibitors (DDRis) may activate T-cell responses and trigger inflammatory cytokines release and eventually immunogenic cancer cell death by amplifying DNA damage and generating immunogenic neoantigens, especially in DDR-defective tumors. DDRi may also lead to adaptive PD-L1 upregulation, providing a rationale for PD-L1/PD-1 blockade. Thus, based on preclinical evidence of efficacy and no significant overlapping toxicity, some ICB/DDRi combinations have rapidly progressed to clinical testing in breast and ovarian cancers. Here, we summarize the available clinical data on the combination of ICB with DDRi agents for treating breast and ovarian cancers and discuss the mechanisms of action and other lessons learned from translational studies conducted to date. We also review potential biomarkers to select patients most likely to respond to ICB/DDRi combination therapy.

Highlights

  • Remarkable progress has been made in the clinical application of cancer immunotherapies harnessing the immune system to identify and eradicate breast and ovarian tumors

  • The rationale for combining immune checkpoint blockade (ICB) with DNA damaging response inhibitors (DDRi) is based on several studies that have demonstrated the critical role of DNA damage response (DDR) in the efficacy of cancer immunotherapy [7]

  • MMR deficiency (MMRd) is characterized by the loss of function of the mismatch repair (MMR) pathway and can generate many insertion and deletion mutations; this indel mutational load has generated a substantial number of immunogenic neoantigens, potentially driving immunotherapeutic responses [12]

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Summary

Introduction

Remarkable progress has been made in the clinical application of cancer immunotherapies harnessing the immune system to identify and eradicate breast and ovarian tumors. Considering that DDR proteins maintain genome integrity, amplifying DNA damage using DDR pathway inhibitors may effectively increase the TMB and neoantigen production, alter the inflammatory milieu of the TME, and trigger immunogenic cancer cell death, subsequently activating antitumor immune responses (Fig. 3).

Results
Conclusion

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