Clin Cancer Res | STAT3 in Treg

David M. Woods, Rupal Ramakrishnan, Andressa S. Laino, Anders Berglund, Kelly Walton, et al.

Clin Cancer Res; 2018

PD-1 blockade induces durable responses in patients with metastatic melanoma and prolongs relapse-free survival in patients with resected melanoma; however, current biomarkers do not consistently associate with patient responses. In this study, the authors investigated the impact of nivolumab therapy on peripheral blood regulatory T cells (Treg) and its relation to patient outcomes. Peripheral blood Tregs and conventional CD4 t T cells from patients with resected high-risk melanoma treated with adjuvant nivolumab were assessed for gene expression changes by RNA-seq. Percentages of circulating Tregs and phosphorylated-STAT3 (pSTAT3) expression levels were assessed by flow cytometry and validated in an independent cohort of active disease patients. Suppressive function of Tregs was assessed in allogeneic mixed lymphocyte reactions. First of all, the authors found that Nivolumab therapy reduces CD4+CD127 low/- CD25+T-cell suppressive function in non-relapsing patients. PD-1 blockade not only increases expression of phosphorylated STAT3 and expression of IL10 in T cells but also Treg numbers. At last, they found that PD-1 and PDL1 blockade reduces while STAT3 inhibition enhances iTreg suppressive function. These results demonstrate that induction of pSTAT3, reduced suppressive function, and a paradoxical increase in Treg proliferation are novel correlates of patient benefit from PD-1 blockade.

Marc Van den Eynde, Bernhard Mlecnik, Gabriela Bindea, et al.

Cancer Cell. 2018

Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. The authors quantified immune cell types of 603 whole-slide metastases and primary colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased T cell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-in-filtrated metastasis had a stronger association with patient outcome than other metastases.