Abstract
In colorectal cancer, immune effectors may be determinative for disease outcome. Following curatively intended combined-modality therapy in locally advanced rectal cancer metastatic disease still remains a dominant cause of failure. Here, we investigated whether circulating immune factors might correlate with outcome. An antibody array was applied to assay changes of approximately 500 proteins in serial serum samples collected from patients during oxaliplatin-containing induction chemotherapy and sequential chemoradiotherapy before final pelvic surgery. Array data was analyzed by the Significance Analysis of Microarrays software and indicated significant alterations in serum osteoprotegerin (TNFRSF11B) during the treatment course, which were confirmed by osteoprotegerin measures using a single-parameter immunoassay. Patients experiencing increase in circulating osteoprotegerin during the chemotherapy had significantly better 5-year progression-free survival than those without increase (78% versus 48%; P = 0.009 by log-rank test). Hence, systemic release of this soluble tumor necrosis factor decoy receptor following the induction phase of neoadjuvant therapy was associated with favorable long-term outcome in patients given curatively intended chemoradiotherapy and surgery but with metastatic disease as the main adverse event. This finding suggests that osteoprotegerin may mediate or reflect systemic anti-tumor immunity invoked by combined-modality therapy in locally advanced rectal cancer.
Highlights
In colorectal cancer, the influence of the tumor microenvironment with its immune effectors for disease outcome is increasingly acknowledged [1]
Array data was analyzed by the Significance Analysis of Microarrays software and indicated significant alterations in serum osteoprotegerin (TNFRSF11B) during the treatment course, which were confirmed by osteoprotegerin measures using a single-parameter immunoassay
As a result of systematic improvements that include multimodal therapy, primarily neoadjuvant chemoradiotherapy (CRT) followed by surgery, long-term local control is commonly achieved in locally advanced rectal cancer (LARC) [3]
Summary
The influence of the tumor microenvironment with its immune effectors for disease outcome is increasingly acknowledged [1]. RANKL-induced signaling is implicated in the antigen-specific interaction between dendritic cells and T lymphocytes, allowing the immune system to recognize and destroy abnormal cells with non-self antigens [19] In this LARC study, systemic immunological markers and the alterations in circulating levels of OPG during the neoadjuvant treatment course were correlated to progression-free survival (PFS) and treatment toxicity as prospectively assessed by Common Terminology Criteria for Adverse Events (CTCAE) scoring, a comprehensive grading system for adverse treatment effects [20]. This approach may provide insight into systemic anti-tumor immunity invoked by combined-modality radiotherapy in a patient population treated with curative intent but with a significant risk of metastatic disease as an adverse outcome
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