Immune System Cancer Research Articles

MicroEpitope: an atlas of immune epitopes derived from cancer microbiomes.

The majority of human cancers harbor molecular evidence of intratumoral microbiota. Microbiota-derived epitopes as molecular mimics of tumor antigens can bind human leukocyte antigen (HLA), thereby modulating host immunity. However, many questions remain regarding the mechanisms underlying the interactions between microbiota and the host's immune system in cancer. Here, MicroEpitope (http://bio-bigdata.hrbmu.edu.cn/MicroEpitope) was developed to provide and analyze the atlas of microbiota-derived epitopes in cancer. We manually collected available mass spectrometry (MS)-based HLA immunopeptidomes of 1190 samples across 24 cancer types. Alignment was performed against an in-house constructed theoretical library of human and intratumor microbiome encoded proteins, including 1298 bacterial and 124 viral species. Currently, MicroEpitope contains 51497 bacteria and 767 virus-derived epitopes, mainly originating from Bacillus subtilis, Buchnera aphidicolaand human cytomegalovirus. The common immunogenic features of epitopes were calculated, as well as their biochemical properties and the clinical relevance of corresponding bacteria and viruses across cancers. MicroEpitope also provides five analytical tools, and multiple visualization methods to facilitate understanding of the roles of microbiota-derived epitopes in cancer immunity. In summary, MicroEpitope represents a vital resource for investigating HLA-presented immunopeptidomes derived from cancer microbiomes, and could further enable rich insight in tumor antigen prioritization strategies.

Recent Advances in Nanomaterial-Based Immunotherapy for Prostate Cancer: A Comprehensive Review

Abstract: Prostate Cancer (PCa) remains a global health concern, and recent advancements in nanomaterial- based immunotherapy are reshaping the landscape of its treatment. The advent of Prostate- Specific Antigen (PSA) screening had a significant impact on the PCa burden until the early 21st century, but the ongoing innovations in therapeutic approaches and early detection methods have contributed to a decline in mortality rates. This comprehensive review delves into the evolving role of the immune system in cancer, with a particular emphasis on the latest advances in nanomaterial- based immunotherapy for PCa. The review focuses on the burgeoning field of nanomaterial- based immunotherapy for PCa, particularly in the context of vaccine-based therapies and immune checkpoint inhibitors. Recent developments in clinical trials highlight the effectiveness of immune checkpoint inhibitors, such as CTLA-4 and PD-1 inhibitors, either as standalone treatments or in combination for metastatic Castration-Resistant Prostate Cancer (mCRPC). We highlight ongoing clinical trials that explore PSMA-targeted CAR-T cells for mCRPC patients, offering valuable insights into the promising field of nanomaterial-based immunotherapy. The review also discusses nanomaterial-based vaccine treatments, such as Sipuleucel-T (Provenge®) and G-VAX. These work in different ways to boost the immune system's response to Tumor-Associated Antigens (TAAs). We also explore viral vector-based vaccines and gene therapy approaches, highlighting their potential to enhance the immune system's ability to target prostate cancer cells at the nanoscale. The article concludes with an in-depth discussion of the current and emerging nanomaterial-based biomarkers for PCa diagnosis and prognosis.

Abstract LB248: Interrogating the cancer-immunity cycle through the lens of a large-scale single-cell atlas of immune checkpoint inhibition response and resistance

Abstract Introduction. The cancer-immunity cycle (CIC; Chen et al. 2013; Mellman et al. 2023) systematizes the current understanding of the factors (both suppressive and promoting) that together determine the anticancer immune responses. While the CIC is not limited to any single therapeutic modality, the framework is useful for understanding the mechanisms of immune checkpoint inhibition (ICI) response and resistance. Given its importance in the field, it is critical to be able to systematically examine and expand the CIC (or related frameworks) using new high-throughput data. Here we intersect the CIC framework with a large-scale atlas of single-cell RNA-seq data to provide a window into the CIC factors supported across multiple tumor types. Approach. We have previously developed the Single-Cell Immune Checkpoint Inhibition Atlas (ICI Atlas) which in its original version spanned 27 datasets and 1.9 million cells across a range of tumor types and ICI therapies. Motivated by rapid growth of data in the field, here we develop version 2 of the Atlas, over twice as large and consisting of 55 datasets and 4.4 million cells with cross-dataset integration via a transformer-based deep learning model. Of the 55 datasets, 47 contain both pre- and post-treatment samples, 2 contain only pre-treatment samples, and 6 contain only post-treatment samples. The Atlas spans 124 cell types and covers 19 different cancer types as well as 31 treatment strategies including 19 ICI therapies. Results. To determine the ICI Atlas support for each factor in the CIC, we analyzed the percent of studies where the factor’s cell type-specific pre-treatment expression was significantly higher in ICI responders (for promoting factors) or in non-responders (for inhibiting factors). We found that 16 cell type-specific CIC factors (12 promoting and 4 inhibiting) had strong support in the ICI Altas (supported in ≥ 50% of relevant studies). Specific steps of the CIC were associated with well-supported promoting factors, e.g. Step 2: interferon alpha/beta signaling pathway (dendritic cells/APCs, 50-100% of studies); Step 3: TCR signaling pathway (T cells; 58%); Step 5: CXCL9/10/11 (macrophages, 50-75%) and CCL5 (T cells, 58%); Step 5a: SELL (T cells, 68%); or inhibiting factors, e.g. Step 5b: IL10 (T cells, 53%). For some factors the support is tissue-specific, e.g. in tumor samples type-I IFN signaling was higher in dendritic cells and monocytes of responders while in blood this was reversed. Interestingly, certain co-stimulatory factors showed higher expression in non-responders (e.g. OX40 in T-cells, 53% of analyses, and 4-1BBL in macrophages, 50%). Our analysis also identifies a number of new factors whose expression is associated with response to ICI across the majority of ICI Atlas studies, providing opportunities for expanding current knowledge of cancer-immune system interplay and ICI response. Citation Format: Piotr Topolewski, Zofia Kochańska, Marlena Osipowicz, Roy Ronen, Janusz Dutkowski. Interrogating the cancer-immunity cycle through the lens of a large-scale single-cell atlas of immune checkpoint inhibition response and resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB248.

The impact of photodynamic therapy on immune system in cancer - an update.

Photodynamic therapy (PDT) is a therapeutic approach that has gained significant attention in recent years with its promising impact on the immune system. Recent studies have shown that PDT can modulate both the innate and adaptive arms of the immune system. Currently, numerous clinical trials are underway to investigate the effectiveness of this method in treating various types of cancer, as well as to evaluate the impact of PDT on immune system in cancer treatment. Notably, clinical studies have demonstrated the recruitment and activation of immune cells, including neutrophils, macrophages, and dendritic cells, at the treatment site following PDT. Moreover, combination approaches involving PDT and immunotherapy have also been explored in clinical trials. Despite significant advancements in its technological and clinical development, further studies are needed to fully uncover the mechanisms underlying immune activation by PDT. The main objective of this review is to comprehensively summarize and discuss both ongoing and completed studies that evaluate the impact of PDT of cancer on immune response.

Sleep disorders and oncological diseases

The study of neurological symptoms and signs connected with neoplasms and antitumor therapy is relevant in the context of an increasing prevalence of cancer. The COVID-19 pandemic and social factors have increased the number of patients suffering from insomnia. Sleep disorders is an unfavorable prognostic factor for neoplasms. The review presents risk factors and mechanisms of sleep disturbance, their relationship with inflammation and dysfunction of the immune system in cancer. In particular, dysfunction of the melatonergic system is discussed as a risk factor for the development of insomnia and cancer. The relevance of developing measures aimed at the rehabilitation of patients in order to restore normal sleep, which plays a fundamental role in maintaining a person's mental and physical health, is emphasized.

Nanomaterials as targeted delivery system of therapeutics for inhibition of cancer

Cancer, a disease with complex pathological process, is the principal cause of mortality and morbidity throughout the world. Conventional chemotherapy faces drawbacks regarding its low bioavaiability, insolubility, high dose requirements, low therapeutic indices, cytotoxicity, multiple drug resistance-development, biological barriers related obstruction, and non-specific targeting. Cancer drug resistance includes over-expression of drug efflux transporters, hypoxic environment, and defective apoptotic pathways. To overcome these discrepancies, a lot of nanomaterials (NMs), as emerging delivery system, have attracted attention for carrying and delivering therapeutics to the desired sites of interest. For improving the targeting potential of the anticancer cargos, NMs are optimized for their sizes, shapes, and surfaces for enhancing their circulation time and targeting efficiency. The NMs through encapsulation or conjugation of cargos with ligands may target them to the cancer site/s with enhanced therapeutic efficacy in a controlled release manner. Generally, NMs, as cancer therapy, are utilized to target cancer cells, tumor microenvironment, and immune system mainly through enhanced permeability and retention (EPR) effect¸­ stimuli-responsive targeting or modifying their surfaces with targeting ligands such as transferin, integrins, sugar, folic acid and antibodies for the enhancement of tissue targeting recognition and their internalization. This review demonstrates mainly the biomedical applications of NMs as delivery vehicles or systems functionalized with ligands and therapeutic agents to target cancer cells / tissues passively, actively or physically with higher inhibitory therapeutic efficacies against cancer.
 Keywords: Cancer; Conventional chemotherapy; Nanomaterials; Biomedical applications; Therapeutic targeting; Inhibitory therapeutic efficacies

Role of stress in the pathogenesis of cancer (Review).

Stress is a state of disrupted homeostasis, triggered by intrinsic or extrinsic factors, the stressors, which are counteracted by various physiological and behavioural adaptive responses. Stress has been linked to cancer development and incidence for decades; however, epidemiological studies and clinical trials have yielded contradictory results. The present review discusses the effects of stress on cancer development and the various underlying mechanisms. Animal studies have revealed a clear link between stress and cancer progression, revealing molecular, cellular and endocrine processes that are implicated in these effects. Thus, stress hormones, their receptor systems and their intracellular molecular pathways mediate the effects of stress on cancer initiation, progression and the development of metastases. The mechanisms linking stress and cancer progression can either be indirect, mediated by changes in the cancer microenvironment or immune system dysregulation, or direct, through the binding of neuroendocrine stress‑related signalling molecules to cancer cell receptors. Stress affects numerous anti‑ and pro‑cancer immune system components, including host resistance to metastasis, tumour retention and/or immune suppression. Chronic psychological stress through the elevation of catecholamine levels may increase cancer cell death resistance. On the whole, stress is linked to cancer development and incidence, with psychological stressors playing a crucial role. Animal studies have revealed a better link than human ones, with stress‑related hormones influencing tumour development, migration, invasion and cell proliferation. Randomized controlled trials are required to further evaluate the long‑term cancer outcomes of stress and its management.

The role of pyroptosis-related lncRNA risk signature in ovarian cancer prognosis and immune system

Ovarian cancer is a leading cause of death in females with gynecologic cancers. Pyroptosis is a relatively new discovered programmed cell death that is believed to be associated with inflammation. However, studies on pyroptosis-related lncRNAs in ovarian cancer are limited. In this study, we identified 29 pyroptosis-related genes and screened out 72 pyroptosis-related lncRNAs. Furthermore, the 72 lncRNAs were eliminated to 2 survival-related lncRNAs using Cox regression and Lasso regression to build an ovarian cancer prognostic prediction signature and were further validated on the test set. We adopted a riskscore from the two-gene signature, and the survival in low-risk group was higher than the high-risk group. Functional enrichment analysis indicated that the differentially expressed genes (DEGs) between two risk groups were associated with tumor immunity. This study implies that pyroptosis-related genes are closely related to tumor immunity and could be potential therapeutic factors for ovarian cancer treatment.

Patient-derived preclinical models to develop immunotherapies.

Cancer immunotherapy has revolutionized the treatment of some malignancies. Yet, many tumors do not unfortunately respond to immune-based therapies. Deeper insights into the biology of the immune response to cancer are required to identify novel therapeutic targets and advance immuno-oncology. To do so, we need to study cancer in patient-derived models that can faithfully recapitulate and capture the complexity and heterogeneity of the tumor immune ecosystem. Platforms facilitating the analysis of the human tumor immune microenvironment of individual patients are crucial. Patient-derived models are fundamental not only to better understand the biology of the cancer immune system but also to discern the mechanism of action of therapeutic compounds and perform preclinical studies toward improving the success of subsequent clinical testing. In this viewpoint, I present a brief review of patient-derived models for cancer immunotherapy.

From Cell–Cell Interaction to Stochastic and Deterministic Descriptions of a Cancer–Immune System Competition Model

We consider a cell–cell interaction model of competition between cancer cells and immune system cells, first introduced in the framework of the thermostatted kinetic theory, and derive a master equation for the probability of the number of cancer cells and immune system cells for a given activity. Macroscopic deterministic equations for the concentrations and mean activities of cancer cells and immune system cells are deduced from the kinetic equations. The conditions for which the 3Es of immunotherapy (elimination, equilibrium, and escape) are reproduced are discussed. Apparent elimination of cancer followed by a long pseudo-equilibrium phase and the eventual escape of cancer from the control of the immune system are observed in the three descriptions. The macroscopic equations provide an analytical approach to the transition observed in the simulations of both the kinetic equations and the master equation. For efficient control of activity fluctuations, the steady states associated with the elimination of either cancer or immune system disappear and are replaced by a steady state in which cancer is controlled by the immune system.

Dissecting the functions of cancer-associated fibroblasts to therapeutically target head and neck cancer microenvironment

Head and neck cancers (HNC) are a diverse group of aggressive malignancies with high morbidity and mortality, leading to almost half-million deaths annually worldwide. A better understanding of the molecular processes governing tumor formation and progression is crucial to improve current diagnostic and prognostic tools as well as to develop more personalized treatment strategies. Tumors are highly complex and heterogeneous structures in which growth and dissemination is not only governed by the cancer cells intrinsic mechanisms, but also by the surrounding tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) emerge as predominant TME components and key players in the generation of permissive conditions that ultimately impact in tumor progression and metastatic dissemination. Although CAFs were initially considered a consequence of tumor development, it is now well established that they actively contribute to numerous cancer hallmarks i.e., tumor cell growth, migration and invasion, cancer cell stemness, angiogenesis, metabolic reprograming, inflammation, and immune system modulation. In this scenario, therapeutic strategies targeting CAF functions could potentially have a major impact in cancer therapeutics, providing avenues for new treatment options or for improving efficacy in established approaches. This review is focused on thoroughly dissecting existing evidences supporting the contribution of CAFs in HNC biology with an emphasis on current knowledge of the key molecules and pathways involved in CAF-tumor crosstalk, and their potential as novel biomarkers and/or therapeutic targets to effectively interfere the tumor-stroma crosstalk for HNC patients benefit. involved in CAF-tumor crosstalk, and their potential as novel biomarkers and/or therapeutic targets to effec- tively interfere the tumor-stroma crosstalk for HNC patients benefit.

Overexpression of CHAF1A is associated with poor prognosis, tumor immunosuppressive microenvironment and treatment resistance.

Background: As distinct marker of proliferating cells, chromatin assembly factor-1 (CAF-1) was critical in DNA replication. However, there is paucity information about the clinical significance, functions and co-expressed gene network of CHAF1A, the major subunit in CAF-1, in cancer. Methods: Bioinformatic analysis of CHAF1A and its co-expression gene network were performed using various public databases. Functional validation of CHAF1A was applied in breast cancer. Results: Overexpression of CHAF1A was found in 20 types of cancer tissues. Elevated expression of CHAF1A was positively correlated with breast cancer progression and poor patients' outcome. The analysis of co-expression gene network demonstrated CHAF1A was associated with not only cell proliferation, DNA repair, apoptosis, but cancer metabolism, immune system, and drug resistance. More importantly, higher expression of CHAF1A was positively correlated with immunosuppressive microenvironment and resistance to endocrine therapy and chemotherapy. Elevated expression of CHAF1A was confirmed in breast cancer tissues. Silencing of CHAF1A can significantly inhibit cell proliferation in MDA-MB-231 cells. Conclusion: The current work suggested that overexpression of CHAF1A can be used as diagnostic and poor prognostic biomarker of breast cancer. Higher expression of CHAF1A induced fast resistance to endocrine therapy and chemotherapy, it may be a promising therapeutic target and a biomarker to predict the sensitivity of immunotherapy in breast cancer.

Effects of lymphopenia on survival in proton therapy with chemotherapy for non-small cell lung cancer.

Lymphocytes play an important role in the cancer immune system. In the present study, we aimed to evaluate the associations of lymphopenia during proton beam therapy (PBT) and concurrent chemotherapy with clinical outcomes and to determine whether lung or bone is more influential on lymphopenia during PBT. Data from 41 patients with stage III non-small cell lung cancer (NSCLC) who received PBT of 74 GyE with concurrent chemotherapy between 2007 and 2017 were reviewed retrospectively. The correlation between dosimetry parameters obtained from dose-volume histograms of the bone and lung and lymphopenia during PBT were analyzed. Minimum absolute lymphocyte count (ALCmin) and maximum neutrophil/lymphocyte ratio (NLRmax) were used as indicators of lymphopenia. Bone V5-20 and lung V5-50 were significantly correlated with the ALCmin and NLRmax during PBT. Multivariable analysis showed that the NLRmax, but not the ALCmin, was associated with overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). The 3-year rates of OS, PFS and DMFS of patients with a low (≤ 6.3) versus high (> 6.3) NLRmax were 73.9% vs 44.4% (P= 0.042), 26.1% vs 5.6% (P= 0.022) and 39.1% vs 5.6% (P< 0.001), respectively. Lung V20 was significantly associated with DMFS on multivariable analyses (hazard ratio: 1.094, P= 0.008), whereas bone V5 had no impact on survival outcomes. We concluded that the NLRmax was a better prognostic indicator than the ALCmin, and the lung dose had more influence than the bone dose on the main survival outcomes in stage III NSCLC patients treated with PBT combined with concurrent chemotherapy.

Comprehensive analysis of prognostic value and immune infiltration of IAPs family in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality rates. The inhibitors of apoptosis (IAP) family act as oncogenes in various tumor types; however, their functions in HCC remain unclear. Here, we used integrated bioinformatics analysis and experimental verification to assess the expression and the prognostic and clinical value of the IAP family in HCC. Using the University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) and the Tumor Immune Estimation Resource (TIMER), we analyzed the expression profiles of IAP family members in HCC tissue, normal tissues, and in patients with different stages and grades of HCC. We further verified the expression level of BIRC2 in 25 HCC samples and matched adjacent normal tissues using quantitative real-time PCR (qRT-PCR), and analyzed its correlation with the marker gene of T-helper type 1 cells (Th1)-STAT1. Meanwhile, the association between BIRC2 and the immunotherapeutic response or immunomodulators was confirmed using the Biomarker Exploration of Solid Tumors (BEST) database. The results showed that NAIP, BIRC2, BIRC3, XIAP, BIRC5, and BIRC6 mRNAs were overexpressed in HCC. The clinical stages, pathological grades, and other clinicopathological features of HCC were closely related to the expression levels of the IAP family members, especially the BIRC2 and BIRC5, which were found to be potential prognostic biomarkers for HCC. Expression of the IAPs was strongly associated with immune cell infiltration. Based on the infiltrative status of various immune cells, HCC patients with high BIRC2 and BIRC5 expression demonstrated poor overall survival (OS) rates. In patients with HCC, BIRC2 expression was noticeably elevated. Concurrently, the expression levels of BIRC2 and STAT1 showed a favorable correlation. BEST database analysis revealed that BIRC2 was a negative predictor of responsiveness to anti-programmed cell death ligand 1 (PD-L1)/cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitor treatment in HCC, and BIRC2 mRNA expression levels were positively correlated with the expression levels of the immune checkpoint genes programmed cell death protein 1 (PD-1), PD-L1, and CTLA-4 in HCC. Consequently, the IAP family may play a role in carcinogenesis and cancer-immune system interactions in HCC. Our results demonstrate that IAP family members may be viable predictive biomarkers and therapeutic targets for HCC.

Breast Cancer Sera Changes in Alu Element Methylation Predict Metastatic Disease Progression.

During metastatic disease development, the cancer-immune system crosstalk induces epigenetic modifications to immune cells, impairing their functions. Recently, Alu elements methylation changes were widely studied in terms of early cancer detection. This study aimed to demonstrate in vitro Alu element methylation changes in peripheral immune cells in a metastatic setting and examine their prognostic values in metastatic breast cancer. Sera from sixteen metastatic cancer patients and sixteen healthy participants were obtained and used to culture normal peripheral immune cells. After 48 h of incubation, the percentage and pattern of Alu element methylation were examined for clinical relevance. We found that the Alu element hypomethylation was affected by age in the cancer group. Intriguingly, a decrease in Alu element methylation was found in patients with early progressive disease. Moreover, an increase in unmethylated cytosine (mCuC) loci was related to the poorer prognosis group. Accordingly, the decrease in Alu element methylation and the increase in mCuC loci pattern in peripheral immune cells correlated with poorer prognosis and early progression in metastatic breast cancer. Alu element hypomethylation in immune cells and their increased mCuC foci were related to the early progression of breast cancer. These warrant the use of Alu element methylation changes for diagnostic and therapeutic purposes in breast cancer.

Decoding the associations between cell functional states in head and neck cancer based on single-cell transcriptome

ObjectivesSystematically identifying cancer cell functional states, especially their associations, is key to understanding the pathogenesis of cancers. Materials and MethodsHere, we systematically identified six cancer-related states, including epithelial-mesenchymal transition (EMT), immune response, epithelial differentiation, stress, G1/S and G2/M phases, in head and neck squamous cell carcinoma (HNSCC) based on single-cell RNA-sequencing (scRNA-seq). Results and ConclusionWe defined the association patterns between these functional states and found the patterns were correlated with the state activity. Particularly, immune response and EMT were negatively, positively, or non-significantly correlated in samples with the highest immune response activity, the lowest activity of the two states, or with the highest EMT activity, respectively. Combining scRNA-seq data of immune cells and four independent HNSCC cohorts, we found the negative relationship between EMT and immune response was correlated with an activated immune microenvironment and a longer survival, while the non-significant relationship was correlated with an immunosuppressed microenvironment and a poor prognosis. Collectively, our results provide insight into the association patterns between functional states in HNSCC, and may facilitate the elucidation of the interactions between cancer cells and immune system during cancer progression.

Intratumoral Heterogeneity and Immune Modulation in Lung Adenocarcinoma in Female Smokers and Never Smokers.

Single-cell analysis of healthy lung tissue and lung cancer reveals distinct tumor cell populations, including cells with differential immune modulating capacity between smokers and never smokers, which could guide future therapeutic strategies.

MicroRNAs at the Crossroad between Immunoediting and Oncogenic Drivers in Hepatocellular Carcinoma.

Simple SummaryIn recent years, treatments enhancing the antitumor immune response have revealed a new promising approach for advanced hepatocellular carcinoma (HCC). Beside favorable results in about one third of patients, much still remains to be done to face primary nonresponse, early, and late disease reactivation. Understanding the mechanisms underneath immune system modulation by immune checkpoint inhibitors in HCC might give additional opportunities for patient selection and combined approaches. MicroRNAs have emerged as relevant modulators of cancer cell hallmarks, including aberrant proliferation, invasion and migration capabilities, epithelial-to-mesenchymal transition, and glycolytic metabolism. At the same time, they contribute to the immune system development, response, and programs activation, with particular regard towards regulatory functions. Thus, miRNAs are relevant not only in cancer cells’ biology, but also in the immune response and interplay between cancer, microenvironment, and immune system.Treatments aimed to reverse the tumor-induced immune tolerance represent a promising approach for advanced hepatocellular carcinoma (HCC). Notwithstanding, primary nonresponse, early, and late disease reactivation still represent major clinical challenges. Here, we focused on microRNAs (miRNAs) acting both as modulators of cancer cell hallmarks and immune system response. We outlined the bidirectional function that some oncogenic miRNAs play in the differentiation and program activation of the immune system development and, at the same time, in the progression of HCC. Indeed, the multifaceted spectrum of miRNA targets allows the modulation of both immune-associated factors and oncogenic or tumor suppressor drivers at the same time. Understanding the molecular changes contributing to disease onset, progression, and resistance to treatments might help to identify possible novel biomarkers for selecting patient subgroups, and to design combined tailored treatments to potentiate antitumor approaches. Preliminary findings seem to argue in favor of a bidirectional function of some miRNAs, which enact an effective modulation of molecular pathways driving oncogenic and immune-skipping phenotypes associated with cancer aggressiveness. The identification of these miRNAs and the characterization of their ‘dual’ role might help to unravel novel biomarkers identifying those patients more likely to respond to immune checkpoint inhibitors and to identify possible therapeutic targets with both antitumor and immunomodulatory functions. In the present review, we will focus on the restricted panel of miRNAs playing a bidirectional role in HCC, influencing oncogenic and immune-related pathways at once. Even though this field is still poorly investigated in HCC, it might represent a source of candidate molecules acting as both biomarkers and therapeutic targets in the setting of immune-based treatments.

Immune signature as a potential marker for predicting response to immunotherapy in obesity-associated colorectal cancer.

It remains unclear whether immunotherapy, which is not generally considered for microsatellite stable (MSS) colorectal cancer (CRC), can be used to effectively treat select CRC patients. We investigated the feasibility of obesity-associated MSS CRC patients for immunotherapy based on genomic alterations. We evaluated differences in genomic alteration types and immune signatures between obese and non-obese patients with MSS CRC. We performed genomic analyses using 434 CRC patients from The Cancer Genome Atlas (TCGA). Patients with MSS CRC were stratified into subgroups based on their BMI and numbers of nonsynonymous single nucleotide variants (nsSNVs) and frameshift insertions and deletions (fs INDELs) using machine learning. The obese subgroup showed higher incidences of single nucleotide variants (SNV) and insertions and deletions (INDELs) in comparison with healthy weight patients with MSS CRC. The subgroup, who had higher numbers of nsSNVs and fs INDLEs, exhibited increased immune signatures, increased number of SNV-derived neoantigens, and had up-regulated two immune checkpoint genes in comparison with healthy weight patients with MSS CRC, reflecting interactions between the cancer genome and immune system. This study suggests that immunotherapy may be suitable for some obesity-associated CRC patients.

Tumor Microenvironment-A Short Review of Cellular and Interaction Diversity.

The tumor microenvironment is a complex network of various interactions between immune cells and non-cellular components such as the extracellular matrix, exosomes and interleukins. Moreover, tumor heterogeneity and its constant modification may alter the immunophenotype and become responsible for its resistance regarding the therapies applied However, it should be remembered that in a strongly immunosuppressive neoplastic microenvironment, the immune system cells undergo reprogramming and most often cease to fulfill their original function. Therefore, understanding what happens within the tumor microenvironment, and which mechanisms are responsible for tumor development and progression should let us know how cancer could protect itself against the immune system. The presented review summarizes the latest information on the interactions between the tumor microenvironment and the cellular and non-cellular components, as well as their impact on cancer development, progression and immune system exhaustion.