Circulating Biomarkers in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus in the Pre-nephrectomy Setting.

Many drugs are available in renal cell carcinoma (RCC), yet clinicians are still looking for predictive biomarkers of disease recurrence or progression supporting more personalised treatments. An assessment of circulating biomarkers over time was carried out in this French, open-label, single-arm, multicentre trial conducted in 25 patients with either locally advanced (n = 14) or metastatic RCC (n = 11) who received everolimus (10 mg daily) for 6 weeks prior to nephrectomy (NEORAD, NCT01715935). Circulating biomarkers, including circulating tumour cells, haematopoietic and endothelial cells, plasma angiogenesis and inflammatory markers were quantified at baseline, upon everolimus and post-nephrectomy. We assessed tumour burden, objective response rate upon RECIST1.1, disease-free survival (DFS) and progression-free survival (PFS). The correlation between circulating biomarkers was evaluated with multiple factor analysis and biomarker association with DFS/PFS by Cox regression. No objective response rate was obtained before nephrectomy. Upon everolimus, neutrophils, platelets and sVEGFR2 significantly decreased. We did not find any association between circulating biomarkers and DFS/PFS, but patients with the highest tumour burden at baseline had significantly higher plasma levels of interleukin-6, an inflammatory circulating biomarker, and lower levels of sVEGFR2, related to angiogenesis. Further understanding of the link between these circulating biomarkers could help to optimise drug combinations in RCC.

Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance.

In immunocompetent individuals, the immune system initially eradicates potentially tumorigenic cells as they develop, a capacity that is progressively lost when malignant cells acquire alterations that sustain immunosubversion and/or immunoevasion. One of the major mechanisms whereby cancer cells block antitumor immune responses involves a specific class of immunosuppressive T cells that-in the vast majority of cases-express the Forkhead box P3 (FOXP3) transcription factor. Such FOXP3(+) regulatory T cells (Tregs) accumulate within neoplastic lesions as a result of several distinct mechanisms, including increased infiltration, local expansion, survival advantage and in situ development from conventional CD4(+) cells. The prognostic/predictive significance of tumor infiltration by Tregs remains a matter of debate. Indeed, high levels of intratumoral Tregs have been associated with poor disease outcome in cohorts of patients affected by multiple, but not all, tumor types. This apparent discrepancy may relate to the existence of functionally distinct Treg subsets, to the fact that Tregs near-to-invariably infiltrate neoplastic lesions together with other cells from the immune system, notably CD4(+) and CD8(+) T lymphocytes and/or to peculiar features of some oncogenic programs that involve a prominent pro-inflammatory component. In this review, we will discuss the phenotype, function and clinical significance of various Treg subsets.