# UVC-Induced Oxidative Stress and DNA Damage Repair Status in Head and Neck Squamous Cell Carcinoma Patients with Different Responses to Nivolumab Therapy

## TL;DR

This study shows that DNA repair and oxidative stress in blood cells from head and neck cancer patients can predict how well they respond to immunotherapy.

## Contribution

The study identifies oxidative stress and DNA repair in PBMCs as potential biomarkers for predicting immunotherapy response in HNSCC patients.

## Key findings

- HNSCC cell lines showed lower DNA repair efficiency and higher oxidative stress compared to normal cells.
- PBMCs from HNSCC patients had increased DNA damage and oxidative stress compared to healthy controls.
- Responders to nivolumab therapy had better DNA repair and lower oxidative stress in PBMCs than non-responders.

## Abstract

Immune-directed therapy reactivates the body’s immune system to fight against cancer cells. In particular, immune checkpoint inhibitors (ICIs), a major class of immunotherapy drugs, have improved survival rates and provided long-lasting results for many cancer patients. However, response rates differ significantly both within and among different types of cancers. Therefore, significant challenges to increasing the response rates and to identifying sensitive and specific biomarkers for responses to ICI treatment remain. Recent data highlight that alterations in the DNA damage repair of the tumor cells can activate an immune response and seem to be associated with patient survival and immunotherapy response. This interesting interplay between the DNA damage repair status and the immune system has opened up new perspectives in clinical studies for cancer treatment. Herein, we found that alterations in the oxidative stress status and the DNA repair capacity of peripheral blood mononuclear cells (PBMCs) from head and neck squamous cell carcinoma (HNSCC) patients at baseline are implicated in the response to subsequent immune checkpoint blockade. If additional studies confirm these findings, they can lead to the development of new predictive biomarkers to immunotherapy in HNSCC and may drive the design of novel ICI-based combination therapies.

Accumulation of evidence highlighted the crosstalk between DNA damage repair and the immune system. Herein, we tested the hypothesis that in head and neck squamous cell carcinoma (HNSCC), the DNA repair capacity of patients’ PBMCs correlates with therapeutic response to immune checkpoint blockade. Following in vitro UVC irradiation, oxidative stress, apurinic/apyrimidinic (AP) lesions, endogenous/baseline DNA damage, and DNA damage repair efficiency were evaluated in three HNSCC (UM-SCC-11A, Cal-33, BB49) and two normal cell lines (RPMI-1788, 1BR-3h-T), as well as in peripheral blood mononuclear cells (PBMCs) from 15 healthy controls (HC) and 49 recurrent/metastatic HNSCC patients at baseline (8 responders, 41 non-responders to subsequent nivolumab therapy). HNSCC cell lines showed lower DNA repair efficiency, increased oxidative stress, and higher AP sites than normal ones (all p < 0.001). Moreover, patients’ PBMCs exhibited increased endogenous/baseline DNA damage, decreased DNA repair capacity, augmented oxidative stress, and higher AP sites than PBMCs from HC (all p < 0.001). Importantly, PBMCs from responders to nivolumab therapy showed lower endogenous/baseline DNA damage, higher DNA repair capacities, decreased oxidative stress, and reduced AP sites than non-responders (all p < 0.05). Together, we demonstrated that oxidative stress status and DNA repair efficiency in PBMCs from HNSCC patients are correlated with the response to immune checkpoint blockade.