Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer

Background:

Foxp3⁺ regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether Tregs play an inhibitory role in chemoradiotherapy (CRT) response in rectal cancer remains unknown.

Methods:

Foxp3⁺, CD3⁺, CD4⁺, CD8⁺ and IL-17⁺ cell density in post-CRT surgical samples from 128 patients with rectal cancer was assessed by immunohistochemistry. The relationship between T-cell subset densities and clinical outcome (tumour regression and survival) was evaluated.

Results:

Stromal Foxp3⁺ cell density was strongly associated with tumour regression grade (P=0.0006). A low stromal Foxp3⁺ cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared with 41% of patients who did not (OR: 7.56, P=0.0005; OR: 5.27, P=0.006 after adjustment for presurgery clinical factors). Low stromal Foxp3⁺ cell density was also associated with improved recurrence-free survival (HR: 0.46, P=0.03), although not independent of tumour regression grade.

Conclusions:

Regulatory T cells in the tumour microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer.     

IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer

Background:

PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear.

Methods:

The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse models under conditions of altering IFN-γ signals was assessed.

Results:

The number of CD8-positive cells in cancer stroma was very high in peritoneally disseminated tumours, and was strongly correlated to PD-L1 expression on the tumour cells (P<0.001). In mouse models, depleting IFNGR1 (interferon-γ receptor 1) resulted in lower level of PD-L1 expression in tumour cells, increased the number of tumour-infiltrating CD8-positive lymphocytes, inhibition of peritoneal disseminated tumour growth and longer survival (P=0.02). The injection of IFN-γ into subcutaneous tumours induced PD-L1 expression and promoted tumour growth, and PD-L1 depletion completely abrogated tumour growth caused by IFN-γ injection (P=0.01).

Conclusions:

Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The lymphocyte infiltration and the IFN-γ status may be the key to effective anti-PD-1 or anti-PD-L1 therapy in ovarian cancer.     

Study of T cell subsets in patients with cutaneous leishmaniasis

Summary The proportion of T lymphocyte populations was assessed using monoclonal antibodies (OKT 3, OKT 4, OKT 8) and spontaneous E-rosette tests with SRBC (for total and active TE cells) in 36 patients with cutaneous leishmaniasis subdivided according to the clinical variety. The T cell profile was normal in patients with simple cutaneous leishmaniasis of early ulcerative type whereas active TE cells and OKT 4 positive cells were reduced in some cases of late ulcerative type. A significant reduction of active TE cells and of OKT 4 positive cells (helper/inducerphenotype) and increase of OKT 8 positive cells (suppressor/ cytotoxic phenotype) was observed in peripheral blood of all patients with persistent active lesions and leishmaniasis recidivans. In patients with highly ulcerated persistent lesions a low proportion of active TE cells was also demonstrated in cellular extracts from dermal tissue. The results support the data obtained in experimental leishmaniasis that lack of helper/inducer cells and generation of suppressor T cells may be responsible for the development of chronic leishmaniasis.     

Mutant p53 promotes epithelial‐mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP‐T mice

To study the postulated mutant p53 (mutp53) “gain of function” effects in mammary tumor development, progression and metastasis, we crossed SV40 transgenic WAP‐T mice with mutant p53 transgenic WAP‐mutp53 mice. Compared to tumors in monotransgenic WAP‐T mice, tumors in bitransgenic WAP‐T x WAP‐mutp53 mice showed higher tumor grading, enhanced vascularization, and significantly increased metastasis. Bitransgenic tumors revealed a gene signature associated with the oncogenic epithelial‐mesenchymal transition pathway (EMT gene signature). In cultures of WAP‐T tumor‐derived G‐2 cancer cells, which are comprised of subpopulations displaying “mesenchymal” and “epithelial” phenotypes, this EMT gene signature was associated with the “mesenchymal” compartment. Furthermore, ectopic expression of mutp53 in G‐2 cells sufficed to induce a strong EMT phenotype. In contrast to these in vitro effects, monotransgenic and bitransgenic tumors were phenotypically similar suggesting that in vivo the tumor cell phenotype might be under control of the tumor microenvironment. In support, orthotopic transplantation of G‐2 cells as well as of G‐2 cells expressing ectopic mutp53 into syngeneic mice resulted in tumors with a predominantly epithelial phenotype, closely similar to that of endogenous primary tumors. We conclude that induction of an EMT gene signature by mutp53 in bitransgenic tumors primarily promotes tumor cell plasticity, that is, the probability of tumor cells to undergo EMT processes under appropriate stimuli, thereby possibly increasing their potential to disseminate and metastasize.     

中国人群中类风湿性关节炎患者外周血T细胞亚群表达的Meta分析

目的：评价类风湿关节炎（RA ）患者外周血T细胞亚群的变化与RA发病机制及疾病发生、发展的关系。方法检索中国生物医学文献数据库、中国知网和万方数据库,收集和筛选符合条件的研究结果,用Meta分析方法进行相关数据统计。结果纳入12篇研究,Meta分析结果显示RA患者的外周血CD3＋、CD4＋、CD8＋T细胞含量所占的比重较对照组差异无显著性（WMD ＝－0．02,95％CI[－0．07,0．02],P＝0．27;WMD ＝0．02,95％CI [0．03,0．08],P＝0．41;WMD ＝－0．03,95％CI[－0．19,0．14],P＝0．74）,但CD4＋／CD8＋比值在类风湿关节炎外周血中较健康组有明显增高（WMD ＝0．81,95％CI[0．74,0．89],P＜0．001）。结论类风湿关节炎患者外周血中,CD4＋／CD8＋比值失衡可能是RA的发病和发展过程的重要机制。