Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape.

Current therapies against cancer utilize the patient's immune system for tumor eradication. However, tumor cells can evade immune surveillance of CD8+ T and/or natural killer (NK) cells by various strategies. These include the aberrant expression of human leukocyte antigen (HLA) class I antigens, co-inhibitory or costimulatory molecules, and components of the interferon (IFN) signal transduction pathway. In addition, alterations of the tumor microenvironment could interfere with efficient antitumor immune responses by downregulating or inhibiting the frequency and/or functional activity of immune effector cells and professional antigen-presenting cells. Recently, microRNAs (miRNAs) have been identified as major players in the post-transcriptional regulation of gene expression, thereby controlling many physiological and also pathophysiological processes including neoplastic transformation. Indeed, the cellular miRNA expression pattern is frequently altered in many tumors of distinct origin, demonstrating the tumor suppressive or oncogenic potential of miRNAs. Furthermore, there is increasing evidence that miRNAs could also influence antitumor immune responses by affecting the expression of immune modulatory molecules in tumor and immune cells. Apart from their important role in tumor immune escape and altered tumor-host interaction, immune modulatory miRNAs often exert neoplastic properties, thus representing promising targets for future combined immunotherapy approaches. This review focuses on the characterization of miRNAs involved in the regulation of immune surveillance or immune escape of tumors and their potential use as diagnostic and prognostic biomarkers or as therapeutic targets.

/pdf/immune-modulatory-micrornas-involved-in-tumor-attack-and-3cwqewptkd.pdf

Immune Modulatory microRNAs Involved in Tumor Attack and Tumor Immune Escape.

HLA-G is a HLA-class Ib molecule with potent immunomodulatory activities, which is expressed in physiological conditions, where modulation of the immune response is required to avoid allograft recognition (i.e., maternal-fetal interface or transplanted patients). However, HLA-G can be expressed de novo at high levels in several pathological conditions, including solid and hematological tumors and during microbial or viral infections, leading to the impairment of the immune response against tumor cells or pathogens, respectively. On the other hand, the loss of HLA-G mediated control of the immune responses may lead to the onset of autoimmune/inflammatory diseases, caused by an uncontrolled activation of the immune effector cells. Here, we have reviewed novel findings on HLA-G functions in different physiological and pathological settings, which have been published in the last two years. These studies further confirmed the important role of this molecule in the modulation of the immune system.

/pdf/recent-advances-in-our-understanding-of-hla-g-biology-hlil8rkwy6.pdf

Recent Advances in Our Understanding of HLA-G Biology: Lessons from a Wide Spectrum of Human Diseases.

It is now well accepted that many tumors undergo a process of clonal selection which means that tumor antigens arising at various stages of tumor progression are likely to be represented in just a subset of tumor cells. This process is thought to be driven by constant immunosurveillance which applies selective pressure by eliminating tumor cells expressing antigens that are recognized by T cells. It is becoming increasingly clear that the same selective pressure may also select for tumor cells that evade immune detection by acquiring deficiencies in their human leucocyte antigen (HLA) presentation pathways, allowing important tumor antigens to persist within cells undetected by the immune system. Deficiencies in antigen presentation pathway can arise by a variety of mechanisms, including genetic and epigenetic changes, and functional antigen presentation is a hard phenomenon to assess using our standard analytical techniques. Nevertheless, it is likely to have profound clinical significance and could well define whether an individual patient will respond to a particular type of therapy or not. In this review we consider the mechanisms by which HLA function may be lost in clinical disease, we assess the implications for current immunotherapy approaches using checkpoint inhibitors and examine the prognostic impact of HLA loss demonstrated in clinical trials so far. Finally, we propose strategies that might be explored for possible patient stratification.

https://jitc.bmj.com/content/jitc/9/8/e002899.full.pdf

Deregulation of HLA-I in cancer and its central importance for immunotherapy.

MicroRNAs (miRNAs) are endogenously encoded ∼22 nt small non-coding RNAs. They function as key players of many cellular processes by base pairing with target mRNAs and thereby impairing gene expression at the post-transcriptional level. Recent findings demonstrate a critical role of many miRNAs in immune cell differentiation and immune responses, which is also associated with the development and progression of many tumor and non-tumor diseases. Here we review the multifaceted miRNA-148/-152 family members consisting of miR-148a, miR-148b and miR-152. Next to regulation mechanisms that control the expression of this miRNA family, we will focus on (i) the role of miR-148a in regulating B and T lymphocyte function and its role in associated diseases and (ii) the importance of miR-148/-152 family members for cancer initiation, tumor growth and metastasis formation. In addition, this review aims to highlight some selected targets of the miRNA-148/-152 family members, which are involved in the biology of cancer and maintenance of epigenetic patterns. In conclusion, members of the miR-148/-152 family might represent prognostic markers and/or potential therapeutic targets for treatment of autoimmune disorders, chronic inflammatory diseases and multiple types of cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.201747132

The role of the miR-148/-152 family in physiology and disease.

The non-classical human leukocyte antigen G (HLA-G) is expressed at a high frequency in renal cell carcinoma (RCC) and is associated with a higher tumor grade and a poor clinical outcome. This might be caused by the HLA-G-mediated inhibition of the cytotoxicity of T and NK cells. Therefore a selective targeting of HLA-G might represent a powerful strategy to enhance the immunogenicity of RCC lesions. Recent studies identified a number of HLA-G-regulating microRNAs (miRs) and demonstrated an inverse expression of some of these miRs with HLA-G in RCC in vitro and in vivo. However, it was postulated that further miRs might exist contributing to the tightly controlled selective HLA-G expression.By application of a miR enrichment assay (miTRAP) in combination with in silico profiling two novel HLA-G-regulatory miRs, miR-548q and miR-628-5p, were identified. Direct interactions of both miRs with the 3' untranslated region of HLA-G were confirmed with luciferase reporter gene assays. In addition, qPCR analyses and immunohistochemical staining revealed an inverse, expression of miR-628-5p, but not of miR-548q to the HLA-G protein in primary RCC lesions and cell lines. Stable overexpression of miR-548q and miR-628-5p caused a downregulation of HLA-G mRNA and protein. This leads in case of miR-548q to an enhanced NK cell-mediated HLA-G-dependent cytotoxicity, which could be reverted by ILT2 blockade suggesting a control of the immune effector cell activity at least by this miR. The identification of two novel HLA-G-regulatory miRs extends the number of HLA-G-relevant miRs tuning the HLA-G expression and might serve as future therapeutic targets.

Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma

Ordered arrays of mixtures of nucleic acid molecules are provided, which mixtures reflect the expression profile of one or more specimens, such as different cells or tissues. In particular embodiments, complete mRNA mixtures from specimens are separately arrayed on a substrate. Specimens from which such mixtures of nucleic acid molecules are produced can be taken from any source, including animal, plant and/or microbial cells, and can be assembled in any collection desired. The collections can, for instance, include different cell types, different phenotypes, cells grown under different conditions, cells of different ages or developmental stages, and so forth. The nucleic acid arrays are provided in both macro- and microarray formats, and are suitable for gene profiling in which relative quantitative expression from a single source or multiple sources may be determined. Techniques are also disclosed for producing high-fidelity, amplified mixtures of nucleic acid molecules using a combination of anti-sense RNA amplification and template-switching synthesis. Amplified mixtures produced using this method can, for instance, be applied to the disclosed arrays. The disclosed arrays allow high throughput analysis of differential gene expression in a specimen (such as a tumor) or a variety of specimens (such as a variety of tumors), and are suitable for automated preparation and analysis.

Gene profiling arrays

A key question that has remained unanswered in the field of tumor immunology is whether the observed tumor-specific immune responses are intrinsically insufficient to induce cancer rejection or—although adequate for this task—are most often counteracted by an evolving disease that is capable of escaping them through continuous phenotypic changes. A combination of the two is probably at the basis of the relatively rare observation of tumor regression in response to immune manipulation. However, in this chapter, we emphasize the importance that the latter possibility may have in influencing the success of most anticancer immunization strategies. We also discuss strategies that may help to understand this complex phenomenon, with the ultimate goal of identifying the true algorithm that modulates the immune rejection of cancer.

The Development and Reversal of T-Cell Tolerance in Cancer Patients Receiving Peptide-Based Vaccines

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Papers

Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma

Gene profiling arrays

The Development and Reversal of T-Cell Tolerance in Cancer Patients Receiving Peptide-Based Vaccines