DNA Damage Repair Pathways

Here at Creative Biolabs, we are delighted to present you with advanced biological insights into DNA damage response (DDR) and its relevant pathways in supporting anti-cancer therapies and tumor immunology.

Introduction of DDR

During physiological processes, cells and DNA endure continuous damage that accumulates over time. Excessively severe damage results in cell death and the development of cancer. The detection and repair of DNA damage are typically managed through one of the following pathways:

Fig.1 Pathways of detection and repair of DNA damage.

DDR and Immune Function

DDR exhibits direct links to inflammation and immunity:

• Chromosomal instability or deficiencies in DDR genes can lead to the accumulation of cytoplasmic DNA, triggering STING activation of type I immune responses.
• DNA damage can activate the pro-inflammatory transcription factor NF-kB via the PARP1 pathway.
• DNA damage induces the phosphorylation of the NF-kB essential modulator (NEMO) through ATM mediation.

Fig.2 DNA damage repair. ¹

DDR and Cancer Progression:

Loss of DNA damage and DDR pathways is expected to increase immune cell infiltration and inflammation within tumors. This observation holds true for patients with defects in multiple DDR pathways and various types of tumors.

• DNA damage can alter exogenous immunogenicity at the tumor microenvironment level.
• By regulating cellular surface phenotypes, deficiencies in DDR pathways make tumors more vulnerable to immune cell killing.
• Persistent DNA damage leads to epigenetic changes and impacts the expression of key immune regulatory proteins on tumor cells.

Given the influence of DDR pathways on immune initiation and tumor pathology, intervening through pivotal DDR pathways holds promise for achieving better prognoses in tumor patients.

Combining DDR Pathway and Checkpoint Blockade

Interventions targeting DDR pathways can be combined with immune checkpoint blockade (ICB) to forge novel immunotherapeutic strategies that disrupt the self-perpetuating cycle of DNA damage and chronic inflammation.

• Under DDR defects, PARP inhibitors have the capacity to reset the inflammatory microenvironment, reestablish Th1 immune responses, and trigger catastrophic DNA damage and subsequent tumor cell death.
• PARP or CHK1 inhibition significantly enhances the anti-tumor effects of PD-L1 blockade, thereby increasing cellular infiltration.
• DDR inhibition can activate the STING/TBK1/IRF3 innate immune pathway, elevate chemokine levels such as CXCL10 and CCL5, and induce cytotoxic T-cell functionality.
• Currently, three distinct combinations of MMR inhibitors/anti-PD-1/L1 have yielded favorable test results, demonstrating excellent tolerability and toxicity profiles.

Predicting the Effects of DDR Damage on Tumor Intervention

In general, high TMB alone does not invariably predict ICB response. Numerous studies have substantiated the fundamental connection between DNA damage and immunogenicity:

• Tumors with DDR defects are expected to have a higher rate of neoantigen formation owing to their elevated mutation burden, rendering them more susceptible to the influence of ICB.
• Specific mutations in DDR pathways can enhance immune responses and potentiate the efficacy of ICB.

In fact, deficiencies in key DDR genes are being considered as candidate predictive biomarkers for selecting more judicious intervention approaches and target patients.

Our Services

Beyond offering theoretical support, Creative Biolabs strives to provide an irreplaceable catalyst for your research through our comprehensive, all-encompassing immune checkpoint services. We aim to explore the intrinsic connections between inflammation and immune responses, providing robust theoretical support to facilitate your exploration of pathways that maximize treatment efficacy through more judicious patient selection and intervention combinations. Contact us now to explore the full potential of our services.

• Custom Immune Checkpoint Protein Development
• Antibody Development for Immune Checkpoints
• Immune Checkpoint Targeted Peptide Development
• Immune Checkpoint Targeted Small Molecule Drug Development
• Immune Checkpoint Assays
• Preclinical Research for Immune Checkpoint Targeting Drugs

Reference

1. Stewart, Pilie, et al. "Development of PARP and Immune-Checkpoint Inhibitor Combinations." Cancer Research. 78.24 (2018): 6717-6725.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.