Immune-checkpoint inhibitors targeting PD-1 or PD-L1 have already substantially improved the outcomes of patients with many types of cancer, although only 20-40% of patients derive benefit from these new therapies. PD-L1, quantified using immunohistochemistry assays, is currently the most widely validated, used and accepted biomarker to guide the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies. However, many challenges remain in the clinical use of these assays, including the necessity of using different companion diagnostic assays for specific agents, high levels of inter-assay variability in terms of both performance and cut-off points, and a lack of prospective comparisons of how PD-L1+ disease diagnosed using each assay relates to clinical outcomes. In this Review, we describe the current role of PD-L1 immunohistochemistry assays used to inform the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies, we discuss the various technical and clinical challenges associated with these assays, including regulatory issues, and we provide some perspective on how to optimize PD-L1 as a selection biomarker for the future treatment of patients with solid tumours.

PD-L1 as a biomarker of response to immune-checkpoint inhibitors

Cancer immunotherapy: Pros, cons and beyond.

c-Jun N-terminal kinase (JNK) is involved in cancer cell apoptosis; however, emerging evidence indicates that this Janus signaling promotes cancer cell survival. JNK acts synergistically with NF-κB, JAK/STAT, and other signaling molecules to exert a survival function. JNK positively regulates autophagy to counteract apoptosis, and its effect on autophagy is related to the development of chemotherapeutic resistance. The prosurvival effect of JNK may involve an immune evasion mechanism mediated by transforming growth factor-β, toll-like receptors, interferon-γ, and autophagy, as well as compensatory JNK-dependent cell proliferation. The present review focuses on recent advances in understanding the prosurvival function of JNK and its role in tumor development and chemoresistance, including a comprehensive analysis of the molecular mechanisms underlying JNK-mediated cancer cell survival. There is a focus on the specific "Yin and Yang" functions of JNK1 and JNK2 in the regulation of cancer cell survival. We highlight recent advances in our knowledge of the roles of JNK in cancer cell survival, which may provide insight into the distinct functions of JNK in cancer and its potential for cancer therapy.

JNK signaling in cancer cell survival.

To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial–mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.

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Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

Reprogramming of cancer metabolism is a newly recognized hallmark of malignancy. The aberrant glucose metabolism is associated with dramatically increased bioenergetics, biosynthetic, and redox demands, which is vital to maintain rapid cell proliferation, tumor progression, and resistance to chemotherapy and radiation. When the glucose metabolism of cancer is rewiring, the characters of cancer will also occur corresponding changes to regulate the chemo- and radio-resistance of cancer. The procedure is involved in the alteration of many activities, such as the aberrant DNA repairing, enhanced autophagy, oxygen-deficient environment, and increasing exosomes secretions, etc. Targeting altered metabolic pathways related with the glucose metabolism has become a promising anti-cancer strategy. This review summarizes recent progress in our understanding of glucose metabolism in chemo- and radio-resistance malignancy, and highlights potential molecular targets and their inhibitors for cancer treatment.

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The roles of glucose metabolic reprogramming in chemo- and radio-resistance.

Cancer-associated fibroblasts (CAFs), one of the principal constituents of the tumor microenvironment, have a pivotal role in tumor progression. Dysregulation of microRNAs (miRNAs) in CAFs contributes to the tumor-promoting ability of CAFs. However, the mechanism underlying the involvement of miRNAs in CAFs of gastric cancer (GC) is not fully understood. This study aimed to explore the effects of miRNA-214 in CAFs on GC migration and invasion. The primary CAFs and corresponding normal fibroblasts (NFs) were isolated. Cell counting kit-8, EdU cell proliferation staining and Transwell assays were used to determine the role of miRNA-214 in GC progression. Real-time polymerase chain reaction, Western blot analysis, and dual-luciferase reporter assay were performed to verify the target genes of miRNA-214. Immunofluorescence and Western blot analysis were applied to detect the expression of epithelial–mesenchymal transition (EMT) markers. Immunohistochemistry and in situ hybridization were implemented to analyze the fibroblast growth factor 9 (FGF9) and miRNA-214 expression in human GC tissues, respectively. Finally, to assess its prognostic relevance, Kaplan–Meier survival analysis was conducted. MiRNA-214 was significantly downregulated in CAFs of GC compared with NFs. The upregulation of miRNA-214 in CAFs inhibited GC cell migration and invasion in vitro but failed to affect proliferation. Moreover, GC cells cultured with conditioned medium from CAFs transfected with miR-214 mimic showed increased expression of E-cadherin and decreased expression of Vimentin, N-cadherin and Snail, indicating the suppression of EMT of GC cells. Furthermore, FGF9 was proved to be a direct target gene of miR-214. The expression of FGF9 was higher in CAFs than that in tumor cells not only in primary tumor but also in lymph node metastatic sites (30.0% vs 11.9%, P < 0.01 and 32.1% vs 12.3%, P < 0.01, respectively). Abnormal expression of FGF9 in CAFs of lymph node metastatic sites was significantly associated with poor prognosis in patients with GC (P < 0.05). This study showed that miR-214 inhibited the tumor-promoting effect of CAFs on GC through targeting FGF9 in CAFs and regulating the EMT process in GC cells, suggesting miRNA-214/FGF9 in CAFs as a potential target for therapeutic approaches in GC.

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Downregulation of miRNA-214 in cancer-associated fibroblasts contributes to migration and invasion of gastric cancer cells through targeting FGF9 and inducing EMT

Gastrointestinal cancers (GI), are a group of highly aggressive malignancies with heavy cancer-related mortalities. Even if continued development of therapy methods, therapy resistance has been a great obstruction for cancer treatment and thereby inevitably leads to depressed final mortality. Peritumoral cancer associated fibroblasts (CAFs), a versatile population assisting cancer cells to build a facilitated tumor microenvironment (TME), has been demonstrated exerting a promotion influence on cancer proliferation, migration, invasion, metastasis, and also therapy resistance. In this review, we provide an update progress in describing how CAFs mediate therapy resistance in GI by various means, meanwhile highlight the crosstalk between CAFs and cancer cells and present some vital signaling pathways activated by CAFs in this resistant process. Furthermore, we discuss the current advances in adopting novel drugs against CAFs and how the knowledge contributing to improved therapy efficacy in clinical practice. In sum, CAFs create a therapy-resistant TME in several aspects of GI progression, although some key problems about distinguishing CAFs subpopulations and controversial issues on pleiotropic CAFs in medication need to be solved for subsequent clinical application. Predictably, targeting therapy-resistant CAFs is a promising adjunctive treatment to benefit GI patients.

Cancer associated fibroblasts tailored tumor microenvironment of therapy resistance in gastrointestinal cancers.

Background: Gastric cancer (GC) is the third leading fatal cancer in the world and its incidence ranked second among all malignant tumors in China. The molecular classification of GC, proposed by the The Cancer Genome Atlas (TCGA), was added to the updated edition (2019) of WHO classification for digestive system tumor. Although MSI and EBV subtypes appeared as ever-increasingly significant roles in immune checkpoint inhibitor therapy, the underlying mechanisms are still unclear. Methods: We systematically summarized the relationship between EBV, d-MMR/MSI-H subtypes and clinicopathological parameters in 271 GC cases. Furthermore, GSE62254/ACRG and TCGA-STAD datasets, originated from Gene Expression Omnibus (GEO) and TCGA respectively, were analyzed to figure out the prognosis related molecular characteristics by bioinformatics methods. Results: Patients with MSI subtype had better prognosis than the MSS subtype (P = 0.013) and considered as an independent biomarker by the univariate analysis (P = 0.017) and multivariate analysis (P = 0.050). While there was no significant difference between EBV positive and negative tissues (P = 0.533). The positive prognostic value conferred by MSI in different cohorts was revalidated via the clinical analysis of GSE62254/ACRG and TCGA-STAD datasets regardless of race. Then key gene module that tightly associated with better status and longer OS time for MSI cases was obtained from weighted gene co-expression network analysis(WGCNA). NUBP2 and ENDOG were screened from the gene cluster and oxidative phosphorylation, reactive oxygen species(ROS) and glutathione metabolism were analyzed to be the differential pathways in their highly expressed groups. Conclusions: Our results manifested the significant prognostic value of MSI in Chinese GC cohort and comparisons with other populations. More opportunities to induce apoptosis of cancer cells, led by the unbalance between antioxidant system and ROS accumulation, lay foundations for unveiling the better prognosis in MSI phenotype through the bioinformatics analysis.

The Better Survival of MSI Subtype Is Associated With the Oxidative Stress Related Pathways in Gastric Cancer.

Cancer associated fibroblasts (CAFs) are a key component of the tumor microenvironment (TME). They play critical roles in the occurrence and development of gastric cancer (GC) through controlling various cytokines secretion and direct cell-to-cell interaction. However, the underlying mechanism of CAFs in tumor progression has not been entirely elucidated. MicroRNAs (miRNAs) as important factors have a central role in the interplay between tumor cell and TME. Recent studies also highlight that the aberrant expression of miRNAs in CAFs is involved in multiple functions in tumorigenesis and malignant process of GC. In this article, we shortly introduce the miRNAs biogenesis and provide an overview of the mechanisms and emerging roles of CAFs-related miRNAs. Focusing on these miRNAs as potential therapeutic targets may bring better treatment effect on GC and other diseases.

Roles of microRNAs in cancer associated fibroblasts of gastric cancer.

Purpose Targeting the PD-1/PD-L1 pathway has emerged as a novel therapy for cancer. To identify rational candidates for anti-PD-1/PD-L1 immunotherapy in gastric cancer (GC), the abundance of PD-L1 expression was evaluated on a kind of biomarker-based molecular classification for shaping prognosis and treatment planning. Methods One hundred and sixty-five GCs were classified into five subgroups using immunohistochemistry (IHC) and in situ hybridization (ISH) methods, based on a panel of seven markers (MLH1, PMS2, MSH2, MSH6, E-cadherin, P53, and Epstein-Barr virus mRNA). The expression of PD-L1 in GC tissues was analyzed immunohistochemically. Results The five categories (Epstein-Barr virus positivity, microsatellite instability, aberrant E-cadherin, aberrant P53 expression, and normal P53 expression) correspond to the reported molecular subgroups for similar proportions and clinicopathologic characteristics. Survival analysis indicated that subgroups with aberrant E-cadherin expression independently predicted a worse prognosis in GC patients (HR=2.51, P=0.010). The clinical and prognostic profiles produced by this stratification in nonintestinal-type GC were distinguishable from those in intestinal-type. Although PD-L1 was not a significant prognostic factor, that more frequent presence of PD-L1-positive in microsatellite instability tumors than other subtypes (P<0.010) hinted at a prolonged clinical course. Moreover, the lowest level of PD-L1 but the highest of Her2 was observed in the group of aberrant P53, namely it was suggested that there was a negative correlation between PD-L1 and Her2 overexpression. Conclusion Different molecular subtypes in GC may have a tendency to react differently to anti-PD-L1/PD-1 immunotherapy or anti-Her2 therapy. A combination of PD-L1 expression and this cost-effective classification strategy would be helpful for predicting prognosis and promoting personalized therapy in clinical practice.

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Wenbin Guan

Papers

Downregulation of miRNA-214 in cancer-associated fibroblasts contributes to migration and invasion of gastric cancer cells through targeting FGF9 and inducing EMT

Cancer associated fibroblasts tailored tumor microenvironment of therapy resistance in gastrointestinal cancers.

The Better Survival of MSI Subtype Is Associated With the Oxidative Stress Related Pathways in Gastric Cancer.

Roles of microRNAs in cancer associated fibroblasts of gastric cancer.

Integrated assessment of PD-L1 expression and molecular classification facilitates therapy selection and prognosis prediction in gastric cancer