PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota. We further clarify the mechanisms of action of these markers and their roles in shaping, being shaped, and/or predicting therapeutic responses. We also discuss a variety of combinations with PD pathway blockade and their scientific rationales for cancer treatment.

PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations

The tumour microenvironment is the primary location in which tumour cells and the host immune system interact. Different immune cell subsets are recruited into the tumour microenvironment via interactions between chemokines and chemokine receptors, and these populations have distinct effects on tumour progression and therapeutic outcomes. In this Review, we focus on the main chemokines that are found in the human tumour microenvironment; we elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and we consider how they affect cancer immunity and tumorigenesis. We also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer.

Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy

New achievements in the realm of nanoscience and innovative techniques of nanomedicine have moved micro/nanoparticles (MNPs) to the point of becoming actually useful for practical applications in the near future. Various differences between the extracellular and intracellular environments of cancerous and normal cells and the particular characteristics of tumors such as physicochemical properties, neovasculature, elasticity, surface electrical charge, and pH have motivated the design and fabrication of inventive “smart” MNPs for stimulus-responsive controlled drug release. These novel MNPs can be tailored to be responsive to pH variations, redox potential, enzymatic activation, thermal gradients, magnetic fields, light, and ultrasound (US), or can even be responsive to dual or multi-combinations of different stimuli. This unparalleled capability has increased their importance as site-specific controlled drug delivery systems (DDSs) and has encouraged their rapid development in recent years. An in-depth understanding of the underlying mechanisms of these DDS approaches is expected to further contribute to this groundbreaking field of nanomedicine. Smart nanocarriers in the form of MNPs that can be triggered by internal or external stimulus are summarized and discussed in the present review, including pH-sensitive peptides and polymers, redox-responsive micelles and nanogels, thermo- or magnetic-responsive nanoparticles (NPs), mechanical- or electrical-responsive MNPs, light or ultrasound-sensitive particles, and multi-responsive MNPs including dual stimuli-sensitive nanosheets of graphene. This review highlights the recent advances of smart MNPs categorized according to their activation stimulus (physical, chemical, or biological) and looks forward to future pharmaceutical applications.

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Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems

The induction of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) is an important immune-evading mechanism used by tumors. However, the exact nature and function of MDSCs remain elusive, especially because they constitute a heterogeneous population that has not yet been clearly defined. Here, we identified 2 distinct MDSC subfractions with clear morphologic, molecular, and functional differences. These fractions consisted of either mononuclear cells (MO-MDSCs), resembling inflammatory monocytes, or low-density polymorphonuclear cells (PMN-MDSCs), akin to immature neutrophils. Interestingly, both MO-MDSCs and PMN-MDSCs suppressed antigen-specific T-cell responses, albeit using distinct effector molecules and signaling pathways. Blocking IFN-gamma or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which nitric oxide (NO) was one of the mediators. In contrast, while IFN-gamma was strictly required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling or NO production. Finally, MO-MDSCs were shown to be potential precursors of highly antiproliferative NO-producing mature macrophages. However, distinct tumors differentially regulated this inherent MO-MDSC differentiation program, indicating that this phenomenon was tumor driven. Overall, our data refine tumor-induced MDSC functions by uncovering mechanistically distinct MDSC subpopulations, potentially relevant for MDSC-targeted therapies.

Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T-CELL suppressive activity

http://if-pan.krakow.pl/pjp/pdf/2012/5_1020.pdf

Nanoparticles as drug delivery systems

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.25777

Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma.

The purpose of this study was to investigate the expression of special AT-rich binding protein 1 (SATB1) and heparanase in human gastric cancer as well as its relationship to the clinicopathologic factors. Specimens from 102 patients who underwent radical gastrectomy between 2000 and 2002 were studied by immunohistochemistry for SATB1 and heparanase expression. SATB1 and heparanase were positively expressed in 48.0% and 51.0% of gastric cancer cases, respectively. The expression of SATB1 and heparanase was significantly correlated with the depth of invasion, tumor-node-metastatsis (TNM) stage, lymph node metastasis, whereas SATB1 expression was also significantly correlated with distant metastasis. Patients with SATB1-negative expression and heparanase-negative expression had higher survival rates than those with SATB1-positive or heparanase-positive expression. Moreover, a positive correlation was found between SATB1 and heparanase. In multivariable analysis, SATB1 expression was also identified as an independent prognostic indicator for gastric cancer. Our results suggest that combined analysis of SATB1 and heparanase expression may have significant value in determining invasion and metastasis of gastric cancer and assessing prognosis in patients with gastric cancer.

Expression of SATB1 and heparanase in gastric cancer and its relationship to clinicopathologic features

Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, has been regarded as a potential therapeutic target for multiple human cancers. In addition, oxidative stress is closely related to all aspects of cancer. We sought to determine the biological function of lithium, one kind of GSK-3β inhibitors, in the process of reactive oxygen species (ROS) production in colorectal cancer. In this study, we analyzed the cell apoptosis and proliferation by cell viability, EdU, and flow cytometry assays through administration of LiCl. We used polymerase chain reaction and Western blotting to establish the effect of GSK-3β inhibition on the nuclear factor-κB (NF-κB) pathway. Results showed administration of LiCl increased apoptosis and the level of ROS in colorectal cancer cells. Furthermore, the underlying mechanisms could be mediated by the reduction of NF-κB expression and NF-κB-mediated transcription. Taken together, our results demonstrated that therapeutic targeting of ROS/GSK-3β/NF-κB pathways may be an effective way for colorectal cancer intervention, although further preclinical and clinical testing are desirable.

/pdf/lithium-chloride-suppresses-colorectal-cancer-cell-survival-3i6snghiw4.pdf

Lithium chloride suppresses colorectal cancer cell survival and proliferation through ROS/GSK-3β/NF-κB signaling pathway.

Special AT-rich sequence binding protein 1 (SATB1), a new type of gene regulator, has been reported to express in various human cancers and may associate with the malignant potential. However, there are few data available on SATB1 expression and its relationship to tumor progression in gastric cancer. The current study was designed to examine the SATB1 expression in gastric cancer and to correlate it with clinical outcome. SATB1 expression was studied by qRT-PCR, western blotting and immunohistochemistry, respectively. The correlations between SATB1 expression and clinicopathological factors were statistically analyzed. SATB1 mRNA expression was significantly up-regulated in gastric cancer specimens as compared with that in normal tissues (P<0.001). Overexpression of SATB1 protein was observed in gastric cancer cell lines by western blotting. Fifty-three (44.9%) cases showed positive staining for the SATB1 proteins by immunohistochemistry. The expression of SATB1 mRNA agreed well with the western blotting and immunohistochemical findings (P<0.001). SATB1 expression was positively correlated with age, depth of invasion, lymph node metastasis, distant metastasis and TNM stage. Moreover, Kaplan-Meier analysis revealed that SATB1 overexpression was associated with a significantly worse survival (P<0.001). Further multivariable analysis indicated that SATB1 expression was an independent prognostic indicator for gastric cancer (P=0.023). In summary, overexpression of SATB1 correlated with metastatic potential of human gastric cancer and would be a novel independent prognostic marker for predicting the outcome of gastric cancer.

/pdf/satb1-is-an-independent-prognostic-marker-for-gastric-cancer-1gxdmsw840.pdf

SATB1 is an independent prognostic marker for gastric cancer in a Chinese population

In previous a study, we had developed a novel thermosensitive magnetic delivery system based on liposomes. This study aimed to evaluate the efficiency of this system for the co-delivery of both drugs and genes to the same cell and its anti-tumor effects on gastric cancer. Doxorubicin (DOX) and SATB1 shRNA vector were loaded into the co-delivery system, and in vitro DOX thermosensitive release activity, targeted gene silencing efficiency, targeted cellular uptake, in vitro cytotoxicity, as well as in vivo anti-tumor activity were determined. The results showed that this co-delivery system had desirable targeted delivery efficacy, DOX thermosensitive release and SATB1 gene silencing. Moreover, the co-delivery of DOX and SATB1 shRNA exhibited enhanced activity to inhibit gastric cancer cell growth in vitro and in vivo, compared to single delivery. In conclusion, the novel thermosensitive magnetic drug and gene co-delivery system has promising application in combined chemotherapy and gene therapy for gastric cancer.

/pdf/co-delivery-of-doxorubicin-and-satb1-shrna-by-p3xcep0gag.pdf

Xiaoming Lu

Papers

Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma.

Expression of SATB1 and heparanase in gastric cancer and its relationship to clinicopathologic features

Lithium chloride suppresses colorectal cancer cell survival and proliferation through ROS/GSK-3β/NF-κB signaling pathway.

SATB1 is an independent prognostic marker for gastric cancer in a Chinese population

Co-delivery of doxorubicin and SATB1 shRNA by thermosensitive magnetic cationic liposomes for gastric cancer therapy.