Combining targeted DNA repair inhibition and immune-oncology approaches for enhanced tumor control

Abstract

Targeted therapy and immunotherapy have revolutionized cancer treatment. However, the ability of cancer to evade the immune system remains a major barrier for effective treatment. Related to this, several targeted DNA-damage response inhibitors (DDRis) are being tested in the clinic and have been shown to potentiate anti-tumor immune responses. Seminal studies have shown that these agents are highly effective in a pan-cancer class of tumors with genetic defects in key DNA repair genes such as BRCA1/2, BRCA-related genes, ataxia telangiectasia mutated (ATM), and others. Here, we review the molecular consequences of targeted DDR inhibition, from tumor cell death to increased engagement of the anti-tumor immune response. Additionally, we discuss mechanistic and clinical rationale for pairing targeted DDRis with immunotherapy for enhanced tumor control. We also review biomarkers for patient selection and promising new immunotherapy approaches poised to form the foundation of next-generation DDRi and immunotherapy combinations.

Keywords: ATR; DDRi-IO; DNA-damage repair; PARP; STING; biomarkers; cGAS-STING; cellular therapy; immune checkpoint blockade; immuno-oncology; mismatch repair deficits.

Figure 1:. DDRi overwhelms cellular DNA damage responses and induces cancer cell death.

Targeted DDRi agents inactivate key DNA repair pathways, causing accumulation of double-stranded DNA breaks. This double-stranded DNA break accumulation, combined with increased dependence on error-prone repair mechanisms, overwhelms cellular damage tolerance and promotes cancer cell death.

Figure 2:. DDRi-induced cancer cell death activates dendritic cells and promotes T-cell mediated anti-tumor responses.

DDRi induces cancer cell death. While cancer cells can die through multiple cellular mechanisms, cell death is mainly characterized as “programmed” or “immunogenic.” Here, programmed cell death refers to a process where cells die, but cell membranes remain intact. Immunogenic cell death, on the other hand, occurs when cells die and their membranes rupture, spilling cellular contents into the tumor microenvironment. During this process, tumor neoantigens and danger associated molecular patterns (DAMPs) are released. Tumor resident dendritic cells are in turn activated by DAMP release and take up released neoantigens. Once activated, dendritic cells present tumor neoantigens to CD4 and CD8 T-cells, generating tumor-specific adaptive immune responses. Importantly, programmed cell death can also generate T-cell responses via dendritic cell activation. Here, dead cells are phagocytosed by dendritic cells. These dendritic cells then display tumor neoantigens to CD4 and CD8 T-cells, promoting their activation.

Figure 3:. DDRi-induced DNA damage generates cytosolic DNA and activates the cGAS/STING pathway.

A) DDRi agents promote DNA damage accumulation in surviving cancer cell populations. Specifically, DDRi promotes double-stranded DNA break accumulation and replication stress. Once formed, double-stranded DNA breaks are often resected in order to initiate repair. Increased DNA resection activity generates excessive double-stranded DNA production and cytosolic DNA accumulation. Furthermore, double-strand breaks that are poorly repaired can promote micronuclei accumulation via chromosomal missegregation. When present, micronuclei also activate the cGAS-STING pathway. B) Cytosolic DNA is sensed by the cGAS-STING pathway. Once bound to dsDNA, cGAS becomes activated and produces cGAMP. cGAMP production in turn activates STING. Activated STING initiates an inflammatory transcriptional program marked by production of Type I IFNs and other cytokines. These cytokines are then secreted into the tumor microenvironment.

Figure 4:. DDRi promotes cGAS/STING signaling, engaging both adaptive and innate anti-tumor immune responses.

A) DDRi induced cytosolic DNA activates the cGAS/STING pathway. Activate STING initiates transcription of Type I IFNs and other inflammatory cytokines. These cytokines are secreted into the tumor microenvironment where they help recruit and activate anti-tumor T-cells. B) Additionally, cGAS-STING signaling drives NKG2D stress ligand display on the surface of cancer cells. When displayed, these ligands help tumor resident NK cells bind to and kill cancer cells. Thus, cGAS-STING signaling helps engage both adaptive and intrinsic anti-tumor immune responses.

Figure 5:. Existing and Novel Immuno-Oncology Strategies.

A) Tumors cells often upregulate inhibitor ligands like PD-L1 to suppress T-cell killing. B) Inhibitory ligand receptor-blocking antibodies, like anti-PD-L1 antibodies, promote immune cell activation and cell death. C) Bi-specific T-cell engager molecules (BiTEs) simultaneously bind a target (CD19 on B-cells for example) and effector cells (typically CD3 on T-cells) promoting co-localization and subsequent activation of tumor-targeting T-cells. D) Cancer-specific T-cells, either harvested and expanded or engineered (TCR T-cells), target tumor-associated antigens using a natural T-cell receptor reacting to antigenic peptides presented on MHC molecules. E) Chimeric antigen receptor (CAR) T-cells contain extracellular protein-specific (CD19 and BCMA for example) antibody-based extracellular domains which activate intracellular T-cell domains upon ligand binding.