3122 - Cellular Senescence Index Predicts Radiotherapy Response and Outcomes in Esophagus Cancer Patients

Z. Zhang¹, J. Yuan², Y. Dong¹, D. Chen³, and J. Yu⁴; ¹Shandong Cancer Hospital and Institute, Jinan, Shandong, China, ²Shandong cancer hospital, Jinan, China, ³Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, ⁴Shandong Cancer Hospital and Institute, Jinan, China

Purpose/Objective(s): Radiotherapy as one of the most important cancer treatments, plays a crucial role in esophagus cancer. Radiotherapy can lead to cellular senescence to recruit immune cells by secreting the senescence-associated secretory phenotype (SASP). Although senescence triggered by radiotherapy may affect the efficacy of radiotherapy, the predictive value as a biomarker of cellular senescence remains largely unknown and deserve our exploration. Therefore, this study aimed to evaluate the clinical value of cellular senescence level as a potential biomarker to predict radiotherapy efficacy and assess the association between radiotherapy-induced senescence with immune infiltration. Materials/

Methods: Serum samples of 35 esophagus cancer patients and tumor tissue samples of 11 esophagus cancer patients prior and post radiotherapy were collected retrospectively. Luminex multiplex assays and multiplex immunofluorescence (mIF) were performed on serum and tumor tissue samples, respectively. We selected 24 candidate SASP proteins for Luminex and designed senescence panel (Pan-CK, p21, p16, laminb1, ?H2AX and DAPI) and immune panel (Pan-CK, CD4, CD8, CD56, Perforin, CD68 and DAPI) for mIF. The endpoints for this analysis were progression free survival (PFS) and overall survival (OS). We calculated the senescence index score for each participant according to the following regression formula: senescence index = ß₁x₁ + ... + ß₂₄x₂₄, where ß is the individual weight and x is the standardized value of each SASP proteins.
Results: We found that tumor cells showed higher mean fluorescence intensity of p21, p16 and ?H2AX and lower that of laminb1 after radiotherapy, which indicated higher senescence level. Meanwhile, radiotherapy significantly increased senescence index in serum samples of esophagus cancer patients (post radiotherapy vs. prior radiotherapy, p<0.05). In the full sample, higher senescence index scores were associated with older age (r = 0.24; P <0.05). Furthermore, our data verified that lower senescence index post radiotherapy, but not prior radiotherapy, were associated with poor PFS (p=0.015 HR=3.801, 95% CI: 1.236 to 11.434). The potential mechanism may be attributed to increased immune infiltration include CD4⁺, CD8⁺ and CD56⁺ cells along with higher cellular senescence.
Conclusion: Our study demonstrates that radiotherapy increases the overall cellular senescence level and high senescence index predicts better prognosis of esophagus cancer patients. In addition, cellular senescence induced by radiotherapy may enhance anti-tumor immunity by increasing immune cells infiltration.