Targeting "aged" immune cells: New strategy to boost immunotherapy in solid tumors

Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor originating from epithelial cells of the head and neck region. Chemoimmunotherapy, a neoadjuvant treatment for locally advanced HNSCC, has significantly improved pathological response rates. However, variable patient responses, overlapping treatment-related toxicities and the emergence of drug resistance limit its efficacy.

In a study published in Nature Medicine, Assoc. Prof. XU Fang from the Shenzhen Institutes of Advanced Technology of the Chinese Academy of Sciences, along with collaborators from Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou National Laboratory, and Harvard Medical School, revealed that immunosenescence plays a key role in the development of treatment resistance, and showed that targeting senescent immune cells improves the effectiveness of immunotherapy.

The researchers first conducted the oral/oropharyngeal squamous cell carcinoma (OOC-001) phase II clinical trial in which 51 patients with resectable HNSCC received neoadjuvant chemoimmunotherapy. They found that 23 patients achieved pathological complete response. Single-cell multi-omics profiling showed that non-responding tumors exhibited prominent features of immunosenescence, including reduced CCR7⁺ CD4⁺ naïve T cells and CD27⁺ memory B cells.

Besides, the researchers tested senolytic drugs in animal models. They found that the combination of dasatinib and quercetin with PD-1 blockade significantly reduced tumor burden and extended survival, surpassing the efficacy of PD-1 inhibitors alone or in combination with chemotherapy. Importantly, the senolytic combination restored naïve T cell function and reversed markers of immune aging.

Moreover, the researchers launched a phase II clinical trial (COIS-01) testing senolytics plus immunotherapy. 24 patients with resectable HNSCC received neoadjuvant treatment with anti-PD-1, dasatinib, and quercetin. The regimen achieved a 33.3% major pathological response rate with markedly lower toxicity compared to chemoimmunotherapy. Only one patient experienced grade 3-4 adverse effects, versus more than half in the chemoimmunotherapy cohort.

This study provides a new strategy for solid tumor immunotherapy, which represents a conceptual and therapeutic breakthrough for oncology.