Gastric Carcinomas with Stromal B7-H3 Expression Have Lower Intratumoural CD8+ T Cell Density

CD8+ T cells are the main effector cells of anti-cancer immune response that can be regulated by various costimulatory and coinhibitory molecules, including members of the B7 family. B7 homolog 3 (B7-H3) appears as a promising marker for immunotherapy; however, its significance in gastric cancer (GC) is unclear yet. We evaluated the spatial distribution of CD8+ T cells in relation to the expression of B7-H3 by double immunohistochemical staining. The level of B7-H3 intensity was scored manually (0–3) and dichotomized into B7-H3-low and B7-H3-high groups. The distribution and density of CD8+ T cells was analysed using whole slide digital imaging. B7-H3 was expressed mainly in the stromal compartment of GC (n = 73, 76% of all cases). Tumours with high expression of B7-H3 showed larger spatial differences of CD8+ T cells (86.4/mm2 in tumour centre vs. 414.9/mm2 in invasive front) when compared to B7-H3-low group (157.7/mm2 vs. 218.7/mm2, respectively) (p < 0.001). This study provides insight into the expression pattern of B7-H3 in GC of Western origin. In GCs with higher level of B7-H3 expression, CD8+ T cells were spatially suppressed in the tumour centre suggesting that B7-H3 might be involved in tumour escape mechanisms from the immune response.

Immunotherapy with Checkpoint Inhibitors for Hepatocellular Carcinoma: Where Are We Now?

Immune checkpoint inhibitors (ICIs) are beginning to show promise in the clinical management of hepatocellular carcinoma (HCC). Most recently, the anti-programmed death protein-1 (PD-1) agent atezolizumab combined with bevacizumab demonstrated superiority to sorafenib in a Phase 3 randomised clinical trial in the frontline setting. Other ongoing trials of immunotherapy for HCC are exploring different drug combinations, such as a double checkpoint blockade with PD-1 and anti-Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents or with tyrosine kinase inhibitors. Moreover, ICIs are being tested in the adjuvant and neoadjuvant settings trying to resolve long-time unmet needs in HCC. The results of the ongoing trials will be critical to understanding the extent of the therapeutic role of ICIs in the complex and multifaceted clinical scenario of HCC. Still, there are some critical points which need further attention to clarify the best use of ICIs in HCC patients. For instance, the actual eligibility rate of patients in the real-life scenario, the prompt identification and correct management of immune-mediated adverse events, the identification of biomarkers predicting response or resistance, and strategies to prevent the tumour escape from ICI effect.

Prognostic value of PD-L1+CD4+ T cells in non-small cell lung cancer (NSCLC) patients treated with a PD-1 inhibitor.

58 Background: One of the tumour escape mechanisms is the expression of programmed cell death-1 (PD-1) receptor on immune cells. Clinical trials have demonstrated that antibodies against PD-L1 or PD-1 molecules induce objective clinical responses in pre-treated patients with NSCLC. In this study, we evaluated the levels of PD-1+ and PD-L1+expressing- immune cells and their association with the clinical outcome in NSCLC patients. Methods: Peripheral blood was collected from 32 advanced/metastatic pre-treated NSCLC patients before anti-PD-1 therapy (Nivolumab). Flow cytometry was performed to identify and quantify PD-1 and PD-L1 expression on circulating immune cells with anti-tumor function (CD4+ and CD8+ T cells, B cells, Dendritic cells) , as well as on immunosuppressivecells [(CD4+ and CD8+ Treg cells, Bregs, Myeloid-derived Suppressor cells (MDSC)]. Correlation between the levels of PD-1+ and PD-L1+-expressing immune cells, as well as their association with overall (OS) and progression-free survival (PFS) was evaluated; high expression of immune cells was defined as the percentage of the cells above the mean value. Results: PD-1 and PD-L1 expression was detected on all tested immune cells with anti-tumor activity. PD-1 expression was found on all immunosuppressive cells, whereas only CD4+ and CD8+ Treg cells and Granulocytic -MDSCs expressed PD-L1. No PD-L1 expression was observed on Bregs and monocytic-MDSCs. There was no correlation of PD-1 or PD-L1-expressing cells with response to anti-PD1 treatment. A significantly decreased PFS was observed in the low CD4+ PD-L1+ T cells group compared with the high CD4+ PD-L1+ group (3.4 months vs. 5.2 months, p=0.03). Univariate analysis for PFS revealed that the low percentages of CD4+ PDL-1+ T cells were prognostic for shorter PFS (HR= 3.1, p=0.04). On the multivariate analysis, low PD-L1+ CD4+T cells were independently associated with decreased PFS (HR: 3.3, p=0.03). Conclusions: These data provide evidence that PD-L1+ expression on peripheral CD4+ T cells was a significant predictor of better PFS in NSCLC patients. Therefore, PD-L1 expression could be used for the selection of patients who might benefit from PD-1/PD-L1 inhibitors.

Mechanisms of tumour escape from immune surveillance

The progressive growth and spread of tumour cells in the form of metastases requires an interaction of healthy host cells, such as endothelial cells, fibroblasts, and other cells of mesenchymal origin with immune cells taking part in innate and adaptive responses within the tumour lesion and entire body. The host cells interact with tumour cells to create a dynamic tumour microenvironment, in which healthy cells can both positively and negatively influence the growth and spread of the tumour. The balance of cellular homeostasis and the effect of substances they secrete on the tumour microenvironment determine whether the tumour has a tendency to grow or disappear, and whether the cells remain within the lesion or are capable of metastasis to other regions of the body. Intercellular interactions also determine the tumour’s susceptibility to radiation or other types of cancer treatment. They may also be a rational explanation for differences in treatment outcomes, in which some metastases regress and others progress in response to the same treatment method.

Dissecting the pathways of tumour escape: " question of life and death?"

Apoptotic pathways are providing important saveguard mechanisms in protection from cancer by eliminating altered and often harmful cells. The disturbances of cell proliferation, differentiation and apoptosis are also found on specific signal-transduction pathways within the tumour cells and between these and the immune system. The article focuses attention on the evolution of the melanocytic naevi in the direction of a dysplastic or tumour cell. The determination of single molecules as prognostic parameters within cancer genesis seems to be problematic. New hopes are being placed on the treatment with TW-37, ABT-737 and TAT-Bim, which, to an extent, are able to support the programmed cell death. The clinical importance of these innovative therapies remains to be seen and should therefore, be viewed with considerable criticism.