Circulating T cell subsets are associated with clinical outcome of anti-VEGF-based 1st-line treatment of metastatic colorectal cancer patients: a prospective study with focus on primary tumor sidedness

Abstract

Background 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. Methods The 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). Results 1) 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. Conclusions The 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. Electronic supplementary material The online version of this article (10.1186/s12885-019-5909-5) contains supplementary material, which is available to authorized users.

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment

“…A combination of FOLFOXIRI with immunotherapy may revolutionize standard clinical care [70][71][72]. The presence of immune cells in the tumor microenvironment of mCRC after first-line chemotherapy treatment can be used to predict potential combinations with immunotherapy [72][73][74]. FOLFOX or FOLFOXIRI treatment triggers immune cell infiltration [74], increases the expression of immune-modulatory receptors and can prime and enhance for some time the immune cell activity at the tumor site [72,74].…”

Tipping the Scales With Zebrafish to Understand Adaptive Tumor Immunity

“…In fact, a significant proportion of tumor-infiltrating CD4 + cells are Tregs ( Kim and Cantor, 2014 ). A high ratio of Tregs to cytotoxic CD8 + T cells is correlated with poor prognosis of patients with multiple cancer types, including pancreatic cancer, ovarian cancer, and colorectal cancer ( Preston et al, 2013 ; Tang et al, 2014 ; Bencsikova et al, 2019 ). Hence, the key to the treatment of solid tumors is to suppress the recruitment of Tregs to the TME or to inhibit their immunosuppressive functions.…”

Regulatory T Cells in Angiogenesis

“…It is worth noting, however, that most of these studies provide evidence of correlation but not causation between Treg levels and VEGF signaling. Most recently, a study by Bencsikova et al (62) demonstrated that the initial level of circulating lymphocytes in patients with metastatic colorectal cancer predicted the clinical outcomes of first-line treatment with bevacizumab, a mAb against VEGF. Interestingly, they also reported that low levels of circulating Tregs were…”