Abstract
BackgroundIn a prospective study with long-term follow-up, we analyzed circulating T cell subsets in patients with metastatic colorectal cancer (mCRC) in the context of primary tumor sidedness, KRAS status, and clinical outcome. Our primary goal was to investigate whether baseline levels of circulating T cell subsets serve as a potential biomarker of clinical outcome of mCRC patients treated with an anti-VEGF-based regimen.MethodsThe study group consisted of 36 patients with colorectal adenocarcinoma who started first-line chemotherapy with bevacizumab for metastatic disease. We quantified T cell subsets including Tregs and CD8+ T cells in the peripheral blood prior to therapy initiation. Clinical outcome was evaluated as progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).Results1) mCRC patients with KRAS wt tumors had higher proportions of circulating CD8+ cytotoxic T cells among all T cells but also higher measures of T regulatory (Treg) cells such as absolute count and a higher proportion of Tregs in the CD4+ subset. 2) A low proportion of circulating Tregs among CD4+ cells, and a high CD8:Treg ratio at initiation of VEGF-targeting therapy, were associated with favorable clinical outcome. 3) In a subset of patients with primarily right-sided mCRC, superior PFS and OS were observed when the CD8:Treg ratio was high.ConclusionsThe baseline level of circulating immune cells predicts clinical outcome of 1st-line treatment with the anti-VEGF angio/immunomodulatory agent bevacizumab. Circulating immune biomarkers, namely the CD8:Treg ratio, identified patients in the right-sided mCRC subgroup with favorable outcome following treatment with 1st-line anti-VEGF treatment.
Highlights
In a prospective study with long-term follow-up, we analyzed circulating T cell subsets in patients with metastatic colorectal cancer in the context of primary tumor sidedness, KRAS status, and clinical outcome
Circulating Regulatory T cells (Tregs), CD8+ Cytotoxic CD8+ T cells (CTLs) and CD8:Treg ratio in metastatic colorectal cancer patients in the context of primary tumor sidedness and KRAS status Relative and absolute numbers of circulating immune cells were quantified in mCRC patients at the initiation of 1st line anti-VEGF-based therapy and were evaluated in the context of primary tumor sidedness and KRAS status
The baseline proportion of Tregs in CD4+ cells was predictive for shorter progression-free survival (PFS) and overall survival (OS) and worse objective response rate (ORR), and the baseline CD8:Treg ratio was predictive for longer PFS and OS
Summary
In a prospective study with long-term follow-up, we analyzed circulating T cell subsets in patients with metastatic colorectal cancer (mCRC) in the context of primary tumor sidedness, KRAS status, and clinical outcome. Our primary goal was to investigate whether baseline levels of circulating T cell subsets serve as a potential biomarker of clinical outcome of mCRC patients treated with an anti-VEGF-based regimen. Regulatory T cells (Tregs) prevent immune hypersensitivity and extensive inflammatory responses. Through their immunosuppressive properties, Tregs can contribute to escape of tumor cells from immune surveillance [9]. In metastatic CRC, as well as other cancer types including breast cancer [19], pancreatic cancer [20], and head-andneck squamous cell cancer [21], elevated numbers of circulating Tregs may be related to worse prognosis
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