Role of Senescence-Associated Biomarkers and Immune Dynamics in Predicting Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer.

OBJECTIVE: Neoadjuvant chemoradiotherapy (nCRT) is one of the standard treatments for locally advanced rectal cancer (LARC). However, the therapeutic responses to this form of treatment greatly vary from one patient to another. In this work, we focused on changes of serum senescence-associated secretory phenotype (SASP) factors and immune cell infiltration post-nCRT in a search for possible predictors of response to nCRT. METHODS: Twenty rectal cancer patients treated with nCRT were included and underwent assessments before (pre-) and after (post-) the treatment. Inflammatory cytokines such as IL-1α, IL-6, and IL-8; chemokines such as CCL5, CXCL1, and CCL2 in serum; and immune cell infiltrations including CD8+, CD4+, and CD206+ macrophages were assessed by ELISA and IHC, respectively. Tumor regressions were evaluated by MSK three-tier TRG grading system. RESULTS: Significant post-nCRT upregulation of IL-6, IL-8, IL-1α, CRP, CCL5, and CXCL1 was found, together with increased CD8+ T cell infiltration in tumor regression responders. IL-1α and CCL2 pre-nCRT levels were promised as predictive biomarkers, given that higher pretreatment levels were associated with lower tumor regression. Increased CD8+ cytotoxic T cell infiltration improved treatment outcome, whereas the changes in CD4+ T cells and M2 macrophages did not reach statistical significance. CONCLUSION: IL-1α, CCL2, and CD8+ T cells, were identified as candidate markers that might monitor nCRT effectiveness in rectal cancer patients. These findings reinforce insights into the tumor microenvironment modulated by SASP components and immune cells and imply the need for larger studies to validate such associations.