Immune Suppressive Cells Research Articles

Overexpression of TREM1 is Associated with the Immune-Suppressive Microenvironment and Unfavorable Prognosis in Pan-Cancer.

Triggering receptors expressed by myeloid cells-1 (TREM1) is a receptor belonging to the immunoglobulin superfamily and plays an important role in pro-inflammation in acute and chronic inflammatory disorders. However, the understanding of the immunomodulatory roles of TREM1 in the tumor microenvironment remains incomplete. The expression patterns of TREM1 mRNA in tumors and adjacent normal tissues were compared by analyzing data obtained from the Genotype-Tissue Expression and The Cancer Genome Atlas datasets. Survival analysis was performed to determine the prognostic value of TREM1. Functional enrichment analysis was applied to decipher the discrepancy in biological processes between high- and low-TREM1 groups across various cancers. The correlation between TREM1 and immune cell infiltration determined by using multiple algorithms was evaluated with the Pearson method. Four independent immunotherapy cohorts were adopted to validate the role of TREM1 as a biomarker. TREM1 was elevated in most cancers as verified with clinical samples. Overexpression of TREM1 was linked with undesirable prognosis in patients. Further analysis revealed that TREM1 was positively correlated with immune response, pro-tumor pathways, and myeloid cell infiltration, while being negatively correlated with CD8+ T cell (including infiltration level and biological processes). Concordantly, tumors with high TREM1 levels were more resistant to immunotherapy. Through connective map analysis, therapeutically potential compounds like tozasertib and TPCA-1 were identified, which can be used synergistically with immunotherapy to improve the poor prognosis of patients with high TREM1 levels. Through a systematic and comprehensive pan-cancer analysis, we demonstrated that overexpression of TREM1 in tumors correlated closely with unfavorable outcome, infiltration of immune-suppressive cells, and immune regulation, which highlights its potential use as a tumor prognostic biomarker and a novel target for immunotherapy.

A Cancer Prevention and Treatment Opportunity

Cancer disease results from mutations leading to apoptosis failure and immune system dysfunction. Because one in two people in developed counties will be diagnosed with cancer in their lifetimes, cancer and metastasis prevention should be ahead of therapies.The immune system in cancer patients is compromised and can be fixed with a reboot. The major oncofetal protein –alpha-feto protein –can deliver toxins instead of nutrients to the immune suppressor cells and kill them. The death of myeloid suppressor cells unleashes the immune attack on cancer cells, cancer stem cells, and metastases. Injectable and oral formulations of alpha-feto protein with toxins provide an opportunity to prevent and treat the disease.

"Open Sesame" to the complexity of pattern recognition receptors of myeloid-derived suppressor cells in cancer.

Pattern recognition receptors are primitive sensors that arouse a preconfigured immune response to broad stimuli, including nonself pathogen-associated and autologous damage-associated molecular pattern molecules. These receptors are mainly expressed by innate myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells. Recent investigations have revealed new insights into these receptors as key players not only in triggering inflammation processes against pathogen invasion but also in mediating immune suppression in specific pathological states, including cancer. Myeloid-derived suppressor cells are preferentially expanded in many pathological conditions. This heterogeneous cell population includes immunosuppressive myeloid cells that are thought to be associated with poor prognosis and impaired response to immune therapies in various cancers. Identification of pattern recognition receptors and their ligands increases the understanding of immune-activating and immune-suppressive myeloid cell functions and sheds light on myeloid-derived suppressor cell differences from cognate granulocytes and monocytes in healthy conditions. This review summarizes the different expression, ligand recognition, signaling pathways, and cancer relations and identifies Toll-like receptors as potential new targets on myeloid-derived suppressor cells in cancer, which might help us to decipher the instruction codes for reverting suppressive myeloid cells toward an antitumor phenotype.

TCF-1 negatively regulates the suppressive ability of canonical and noncanonical Tregs.

Regulatory T cells are suppressive immune cells used in various clinical and therapeutic applications. Canonical regulatory T cells express CD4, FOXP3, and CD25, which are considered definitive markers of their regulatory T-cell status when expressed together. However, a subset of noncanonical regulatory T cells expressing only CD4 and FOXP3 have recently been described in some infection contexts. Using a unique mouse model for the first time demonstrated that the TCF-1 regulation of regulatory T-cell suppressive function is not limited to the thymus during development. Our data showed that TCF-1 also regulated regulatory T cells' suppressive ability in secondary organs and graft-vs-host disease target organs as well as upregulating noncanonical regulatory T cells. Our data demonstrated that TCF-1 regulates the suppressive function of regulatory T cells through critical molecules like GITR and PD-1, specifically by means of noncanonical regulatory T cells. Our in vitro approaches show that TCF-1 regulates the regulatory T-cell effector-phenotype and the molecules critical for regulatory T-cell migration to the site of inflammation. Using in vivo models, we show that both canonical and noncanonical regulatory T cells from TCF-1 cKO mice have a superior suppressive function, as shown by their ability to control conventional T-cell proliferation, avert acute graft-vs-host disease, and limit tissue damage. Thus, for the first time, we provide evidence that TCF-1 negatively regulates the suppressive ability of canonical and noncanonical regulatory T cells. These findings provide evidence that TCF-1 is a novel target for developing strategies to treat alloimmune disorders.

PTPN18 Serves as a Potential Oncogene for Glioblastoma by Enhancing Immune Suppression.

Glioblastoma is characterized as one of the deadliest cancers in humans. The survival time is not improved by standard treatment. Although immunotherapy has revolutionized cancer treatment, the current therapy targets for glioblastoma patients are not satisfied. We systematically analyzed the expression patterns, predictive values, and immunological characteristics of PTPN18 in glioblastoma. The independent datasets and functional experiments were employed to validate our findings. Our data showed that PTPN18 is potentially cancerogenic in glioblastoma with advanced grades and poor prognosis. High expression of PTPN18 correlated with CD8+ T cell exhaustion and immune suppression in glioblastoma. In addition, PTPN18 facilitates glioblastoma progression by accelerating glioma cell prefiltration, colony formation, and tumor growth in mice. PTPN18 also promotes cell cycle progression and inhibits apoptosis. Our results illustrate the characterization of PTPN18 in glioblastoma and highlight the potential value as an immunotherapeutic target for glioblastoma treatment.

Prognostic role of immune environment in luminal B early breast cancer.

The importance of the immune microenvironment in triple negative and HER2-amplified breast cancer (BC) is well-established; less is known about the immune environment in luminal breast cancers. We aimed to assess for the impact of immune biomarkers on BC outcome in a group of luminal B patients with archived tissue and annotated clinical information. Patients with early breast cancer (EBC) treated in a single institution over a 14-year period, with prospectively collected data were included. Luminal B EBC patients were identified and defined into three cohorts: A: grade 2 or 3, ER & PR positive, HER2-negative; B: Any grade, ER positive, PR and HER2-negative (Ki67 ≥ 14% in cohorts A & B); and C: Any grade, ER or PR positive, HER2-positive. Within each cohort, patients with a relapsed BC event (R) were compared on a 1:1 basis with a control patient (C) who remained disease-free, balanced for key characteristics in an effort to balance the contribution of each clinical group to outcome. Archival breast, involved and uninvolved axillary nodes were assessed by immunohistochemistry for biomarkers identifying effector and suppressor immune cells, and compared between R and C. In total, 120 patients were included (80, 22, and 18 patients in cohorts A, B, and C, respectively). R were 1.5 years older (p=0.016), with all other characteristics being balanced. Overall, there were no statistically significant differences in immune biomarkers in breast or nodal tissue of R and C. However, there was a trend toward higher levels of TILs in breast tumors of C, while GAL-9 was consistently expressed on lymphocytes and tumor cells in all breast and nodes of C and was absent from all tissues of R. These trends in checkpoint molecule expression deserve further research.

ZNF385A and ZNF346 Serve as Prognostic Biomarkers Associated with an Inflamed Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) has a high mortality rate worldwide, and there are still many problems in the early diagnosis, molecular targeted therapy, and immunotherapy. It is necessary to explore valuable diagnostic markers and new therapeutic targets in HCC. Zinc finger protein 385A (ZNF385A) and zinc finger protein 346 (ZNF346) represent a unique class of RNA-binding Cys2 His2 (C2H2) zinc finger proteins that are involved in the regulation of cell cycle and apoptosis, but little is known of their roles in HCC. Based on multiple databases and analysis tools, we explored the expression, clinical relation, prognostic value, possible biological function, and pathways of ZNF385A and ZNF346, and their relationship with immune infiltration. Our results revealed that ZNF385A and ZNF346 were highly expressed and were associated with poor prognosis in HCC. Hepatitis B virus (HBV) infection may lead to the overexpression of ZNF385A and ZNF346, which was accompanied by elevated apoptosis and chronic inflammation. Moreover, ZNF385A and ZNF346 were positively correlated with immune-suppressive cells, inflammatory cytokines, immune checkpoint genes, and poor immunotherapy efficacy. Finally, the knockdown of ZNF385A and ZNF346 was observed to negatively affect the proliferation and migration of HepG2 cells in vitro. In conclusion, ZNF385A and ZNF346 are promising candidate biomarkers for the diagnosis, prognosis, and response to immunotherapy in HCC, and this study may help to understand the tumor microenvironment (TME) of liver cancer, and to develop new therapeutic targets.

Targeted Therapy of Interleukin-34 as a Promising Approach to Overcome Cancer Therapy Resistance.

Chemotherapy and immunotherapy have markedly improved the management of several malignancies. However, not all cancer patients respond primarily to such therapies, and others can become resistant during treatment. Thus, identification of the factors/mechanisms underlying cancer resistance to such treatments could help develop novel effective therapeutic compounds. Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) are major components of the suppressive tumor microenvironment and are critical drivers of immunosuppression, creating a tumor-promoting and drug-resistant niche. In this regard, therapeutic strategies to tackle immunosuppressive cells are an interesting option to increase anti-tumor immune responses and overcome the occurrence of drug resistance. Accumulating evidence indicates that interleukin-34 (IL-34), a cytokine produced by cancer cells, and/or TAMs act as a linker between induction of a tumor-associated immunosuppressive microenvironment and drug resistance. In this article, we review the current data supporting the role of IL-34 in the differentiation/function of immune suppressive cells and, hence, in the mechanisms leading to therapeutic resistance in various cancers.

The role of tolerogenic dendritic cells in systematic lupus erythematosus progression and remission.

Systematic lupus erythematosus (SLE) is an autoimmune disease reflecting an imbalance between effector and regulatory immune responses. Dendritic cells (DC) are a link between innate and adaptive immunity. Inflammatory DCs (inflDC) can initiate and trigger lymphocyte responses in SLE with over-expression of surface molecules and pro-inflammatory cytokine, including Interferon (IFN) α, Interleukin (IL) 1α, IL-1β, and IL-6, resulting in the overreaction of T helper cells (Th), and B cells immune responses. On the opposite side, tolerogenic DCs (tolDC) express inhibitory interacting surface molecules and repressive mediators, such as IL-10, Transforming growth factor beta (TGF-β), and Indoleamine 2, 3-dioxygenase (IDO), which can maintain self-tolerance in SLE by induction of regulatory T cells (Treg), T cells deletion and anergy. Hence, tolDCs can be a therapeutic candidate for patients with SLE to suppress their systematic inflammation. Recent pre-clinical and clinical studies showed the efficacy of tolDCs therapy in autoimmune diseases. In this review, we provide a wide perspective on the effect of inflDCs in promoting inflammation and the role of tolDC in the suppression of immune cells' overreaction in SLE. Furthermore, we reviewed the finding of clinical trials and experimental studies related to autoimmune diseases, particularly SLE.

Effect of pulsed magnetic field in murine T lymphoma EL4 cells

Maintenance of homoeostasis in human body is a very important indicator in all cell activities. When exposed to a disease, various immune cells are activated due to the inflammatory response, and particularly T cells play a role in inducing apoptosis of mutated cells such as tumor cells. When the activity of T cells is very low, infection by external invasion is easy, and on the contrary, excessive activation leads to chronic inflammation caused by autoimmune diseases. Many clinical studies related to pulsed magnetic field (PMF) demonstrated its efficacy in reducing pain, improving blood circulation, as well as blood’s acid-base balance. Therefore, our study has tried to investigate the influence of PMF on the regulation of acid-base homeostasis in EL4 T lymphoma cell. In addition, we have tried to explain the role of PMF on immune cell activity by measuring the level of pro-inflammatory cytokine, TNF-α in culture supernatants. EL4 cells were cultured in a DMEM medium supplemented with 10% FBS and 1% penicillin in an incubator at 37 °C and 5% CO2 condition. Our PMF stimulator has the maximum strength of 4700 G at a transition time of 222 μs with pulse intervals of 1 Hz. The homoeostasis in pH was improved as PMF strength increases. Cell viability decreased by 32% after PMF stimulation of 4700 G. It was observed that the concentration of TNF-α, a cytokine related to inflammation, also decreased as the strength of PMF increased. These results suggest that PMF stimulation improves the anti-inflammatory effect, therefore, it is thought to affect the immune system by balancing the activation and suppression of immune cells. For clinical use, our study might suggest non-invasive PMF can be developed as a medical devices modulating immune system, although it is necessary to optimize the PMF conditions such as pulse shape, duration, or repetition rate.

Inhibition of myeloperoxidase enhances immune checkpoint therapy for melanoma

BackgroundThe presence of a highly immunosuppressive tumor microenvironment has limited the success of immune checkpoint therapy (ICT). Immune suppressing myeloid cells with increased production of reactive oxygen species are critical...

Evaluating tumor cell- and T cell-derived extracellular vesicles as potential biomarkers of cancer and immune cell competence

ABSTRACT Introduction Extracellular vesicles (EVs) produced by tumors, also called tumor-derived exosomes (TEX), have been implicated in inducing immune cell suppression in vitro and in vivo. The development of a novel category of noninvasive biomarkers for precision oncology remains an unmet need, and TEX emerge as a promising liquid tumor biopsy component. Areas covered TEX play a critical role in monitoring cancer presence/progression and in reprograming of anti-tumor effector T cells to producers of EVs with pro-tumor activity. TEX are a subset of circulating EVs. Their separation by immune capture from EVs derived from nonmalignant cells allows for TEX phenotypic/functional assessments. TEX cross-talking with CD3(+) T cells induce the release of CD3(+) small EV (sEV), whose cargo of suppressor proteins resembles that of TEX and further contributes to cancer-induced immune suppression. While TEX recapitulate the genetic/molecular phenotype of tumor cells, CD3(+) sEV might serve as ‘T cell liquid biopsy.’ Expert opinion Preclinical explorations of the role in cancer body fluids of TEX and CD3(+) sEV as cancer biomarkers suggest that these EV subsets may qualify as liquid tumor biopsy noninvasive components in the near future. Their potential to simultaneously serve as noninvasive liquid tumor biopsy and T cell biopsy remains to be validated in future clinical trials.

Examination of antagonistic metabolic reactions and nicotinamide/methylnicotinamide as a biomarker in gastric cancer.

442 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the therapy pattern of advanced gastric cancer (GC), but the efficacy is still unsatisfactory. The role of metabolism in the immune landscape of tumor microenvironment (TME) has been emphasized for the past few years. As the mediators of cellular interactions in TME, more metabolic biomarkers and their predictive value remain to be revealed. Methods: Metabolite activity scoring gene sets were constructed based on metabolite-protein interaction network. Integrated metabolite profile was collected from metabolic reactions in KEGG database. Transcriptome of ACRG (n=299) and anti-PD-1 cohort (PRJEB25780, n=45) were utilized to generate metabolite activity scores via GSVA algorithm. Cox regression was performed to calculate the hazard ratio (HR) to overall survival of metabolites in each metabolic reaction. Plasma samples (n=55) were obtained to measure nicotinamide metabolites from GC patients in Nanfang Hospital before and after ICIs treatment. Results: 78 metabolic reactions (78/6429) with opposite prognostic value among metabolic substrates and products were identified via the antagonistic metabolism screening workflow. Notably, nicotinamide (NAM)-methylnicotinamide (MNAM) (KEGG REACTION: R01269) showed significant antagonistic relationship (NAM, HR=0.76, 95% CI: 0.64-0.89, P<0.001; MNAM, HR=1.28, 95% CI: 1.09-1.49, P=0.002). NNMT, the rate-limiting enzyme catalyzing the formation of MNAM from NAM, was also correlated with poor prognosis (log-rank P=0.013). In terms of therapeutic prediction, NAM/MNAM ratio in plasma of GC patients was significantly correlated with anti-PD-1 response (PR vs SD/PD, median NAM/MNAM ratio (ng·mL-1/ng·mL-1) = 26.76 vs 10.40, P<0.0001). Compared with baseline, decreased plasma NAM/MNAM ratio was found in all (7/7) PR patients ( P=0.0011), while 73.33% (11/15) of non-responders showed a higher NAM/MNAM ratio after ICIs treatment ( P=0.0283). Correlation analysis of key metabolites with TME cells revealed that MNAM activity score was positively correlated with fibroblasts, MDSCs and M2 macrophages infiltration (Pearson correlation: R=0.60, P<0.001; R=0.42, P<0.001; R=0.34, P<0.001), suggesting that MNAM has a potential impact on immune-suppressive cells recruitment and functions. Conclusions: Nicotinamide metabolism was an indicator of prognosis in GC patients. Circulating NAM/MNAM ratio can be a novel metabolic biomarker in dynamic monitoring for ICIs therapy.

P035 Anti-inflammatory Effect and Mechanism of Action of BMC333, a Rationally-Designed Live Bacterial Consortium Based on Microbiome Functional Genomic Analysis for Treating IBD

Abstract Background The mechanisms by which the intestinal microbiome drives inflammation and disease activity in IBD is not clear. Most of the current efforts in developing treatments targeting the intestinal microbiome in IBD are focused on microbial taxa and very few treatments are developed based on microbiome functions in this condition. Using high-resolution functional microbiome analysis we have designed a live bacterial consortium consisting of four bacterial strains with anti-inflammatory functions (BMC333); and demonstrated the significant anti-inflammatory effects of this consortium in a mouse model of DSS-induced colitis by improving disease activity index, colon length, histologic score and fecal lipocalin (presented at DDW 2022). Aim To validate the anti-inflammatory effects and mechanisms of action of BMC333 using IL10-reporter mouse model. Methods Germ free mice bearing the IL10-GFP reporter gene (B6. IL10-GFP) were orally gavaged with BMC333 at 109 CFU/strain or vehicle/placebo (n=6 in each group) at experimental days 1 and 4. The induction period was followed by 10 days without intervention and the animals were sacrificed at day 14. Immunologic effects was assessed in mouse splenocytes and lamina propria by I. quantitating lamina propria immune-suppressive cells using flow cytometry. II. Comparing the effect of stimulation with each of BMC333 bacterial strains’ lysates on IL10- and IFNγ production by splenocytes from BMC333 or vehicle-treated mice. Results Treatment with BMC333 resulted in: I. Higher levels of immune-suppressive cells (IL10-expressing CD4 T cells and B cells, and regulatory T-cells) in the lamina propria of mice treated with BMC333 compared with vehicle-treated mice. II. Higher numbers of IL10-expressing splenic immunocytes stimulated with lysates compared to non-stimulated cells. Additionally, splenocytes stimulated by each of the BMC333 bacterial strains secreted higher IL10 levels, whereas the strain lysates did not induce secretion of the pro-inflammatory cytokine IFNγ, as measured by ELISA. Conclusion These results validate the anti-inflammatory effects of BMC333 and indicate that this beneficial effect is, at least partially, mediated by increasing IL-10 anti-inflammatory activity as demonstrated by the increased numbers of IL-10-producing lamina propria T and B cells after in vivo colonization, and higher IL-10 producing cells and secretion by BMC333 lysate-stimulated splenocytes. BMC333 stimulates increased immuno-suppressive cell populations in the lamina propria, but no increased production of the pro-inflammatory cytokine IFNγ. These findings are consistent with our previously reported in vivo studies and provide a strong rationale for further development of BMC333 as an effective treatment for IBD.

P096 Characterization of suppressive immune cell subsets in mouse models of colitis-associated colorectal cancer

Abstract Background Chronic colonic inflammation in inflammatory bowel disease (IBD) patients increases the risk of colitis-associated cancer (CAC). Cancer development in CAC is different from that observed in sporadic colorectal cancer (CRC). Most studies have focused on the role of pro-inflammatory immune cell subsets in CAC, yet it is becoming increasingly clear that immunosuppression may also drive cancer progression. We hypothesize that emergence of immunosuppressive cell subsets as a result of chronic intestinal inflammation, dampens anti-tumor immune responses and accelerates the development of CAC. Methods To simulate cancer formation in the background of chronic inflammation, mice were treated with azoxymethane (AOM) followed by three cycles of dextran sodium sulphate (DSS). Apc Min/+ mice treated with AOM were used to model sporadic CRC. After 10 weeks, immune cells from the proximal and distal colonic lamina propria, mesenteric lymph nodes (MLNs) and tumors were obtained for microscopy analyses and processed to obtain single cell suspensions for flow cytometry. Immune cell populations were studied by conventional flow cytometry and immunofluorescence. Results We observed a significant increase in absolute numbers of PD1+CTLA4+TIM3+ ‘exhausted’ CD4+ T cells in the lamina propria from proximal colons in CAC mice as compared to sporadic CRC mice. Interestingly, these numbers showed a positive correlation with the inflammation score in AOM/DSS, demonstrating that chronic inflammation is associated with the emergence of ‘exhausted’ T cells. In addition, we observed a trend to higher numbers of M2-like (MHCII-CD206+) suppressive macrophages and CD4+FoxP3+ regulatory T cells (Tregs) in tumors from CAC mice compared to sporadic CRC. When analysing T cell immune responses in the MLNs, we found a significant decrease in the ratio IFNγ/IL10-producing CD8+ T cells in CAC mice as compared to CRC mice, suggesting a shift towards an anti-inflammatory T cell response in CAC. Conclusion In summary, suppressive immune cell subsets were increased in colonic mucosa and tumors from CAC mice as a result of chronic inflammation, which may be associated with the development of dysplasia. Further functional studies are necessary to prove the role of suppressive immune subsets in IBD-associated dysplasia- and carcinoma progression.

Reactivation of Anticancer Immunity by Resetting Interorgan Crosstalk in Immune-Suppressive Cells with a Nanoparticulated Anti-Inflammatory Drug.

The reactivation of anticancer immunity is a fundamental principle in cancer immunotherapy as evidenced by the use of immune checkpoint inhibitors (ICIs). While treatment with the ICIs is shown to have remarkable and durable therapeutic effects in the responders, the low objective response rate (<40%) continues to be a major problem. Since myeloid-derived suppressor cells (MDSCs), heterogenous cells with strong immunosuppressive activity that originate in the hematopoietic system, suppress the anticancer immunity via parallel immune checkpoint-dependent and independent pathways, these cells are potential targets for improving the efficacy of cancer immunotherapy. In this study, it is demonstrated that MDSCs can be depleted by delivering synthetic glucocorticoid dexamethasone to phagocytic cells in the spleen using a lipid nanoparticle. Since the interaction of nanoparticles with T cells is intrinsically poor, this strategy also enables the "detargeting" from T cells, thus avoiding the nonspecific suppression of cytotoxic immune responses against cancer cells. In addition to the direct anticancer effect of the nanoparticulated dexamethasone, their synergistic anticancer effect with ICIs is also reported.

Bright future or blind alley? CAR-T cell therapy for solid tumors.

Chimeric antigen receptor (CAR) T cells therapy has emerged as a significant breakthrough in adoptive immunotherapy for hematological malignancies with FDA approval. However, the application of CAR-T cell therapy in solid tumors remains challenging, mostly due to lack of suitable CAR-T target antigens, insufficient trafficking and extravasation to tumor sites, and limited CAR-T survival in the hostile tumor microenvironment (TME). Herein, we reviewed the development of CARs and the clinical trials in solid tumors. Meanwhile, a "key-and-lock" relationship was used to describe the recognition of tumor antigen via CAR T cells. Some strategies, including dual-targets and receptor system switches or filter, have been explored to help CAR T cells matching targets specifically and to minimize on-target/off-tumor toxicities in normal tissues. Furthermore, the complex TME restricts CAT T cells activity through dense extracellular matrix, suppressive immune cells and cytokines. Recent innovations in engineered CARs to shield the inhibitory signaling molecules were also discussed, which efficiently promote CAR T functions in terms of expansion and survival to overcome the hurdles in the TME of solid tumors.

Peptide-assembled nanoparticles targeting tumor cells and tumor microenvironment for cancer therapy.

Tumor cells and corrupt stromal cells in the tumor microenvironment usually overexpress cancer-specific markers that are absent or barely detectable in normal cells, providing available targets for inhibiting the occurrence and development of cancers. It is noticeable that therapeutic peptides are emerging in cancer therapies and playing more and more important roles. Moreover, the peptides can be self-assembled and/or incorporated with polymeric molecules to form nanoparticles via non-covalent bond, which have presented appealing as well as enhanced capacities of recognizing targeted cells, responding to microenvironments, mediating internalization, and achieving therapeutic effects. In this review, we will introduce the peptide-based nanoparticles and their application advances in targeting tumor cells and stromal cells, including suppressive immune cells, fibrosis-related cells, and angiogenic vascular cells, for cancer therapy.

Immune Cell Metabolism and Immuno-Oncology

With the significant successes of immune checkpoint blockade and adoptive cellular therapy, immunotherapy has now become an established treatment option to effectively treat cancer. However, the full potential of this treatment modality has yet to be realized, as there are many additional mechanisms whereby tumors continue to evade immune destruction. To this end, metabolic reprogramming by cancer cells serves not only to promote their own growth but also to create an immunosuppressive tumor microenvironment. The tumor metabolic microenvironment not only inhibits antitumor effector function but also supports the differentiation and function of suppressive immune cells. In this review, we delineate the major metabolic programs of cancer cells and immune cells. Furthermore, we discuss the role of so-called metabolic checkpoints that promote immune evasion and tumor growth. Finally, we review current and potential future strategies to target metabolism in order to not simply inhibit tumor growth but also enhance antitumor immune responses. Such strategies have the great potential to enhance the breadth and depth of immunotherapy for cancer by targeting metabolic checkpoints.

Upregulation of CENPM is associated with poor clinical outcome and suppression of immune profile in clear cell renal cell carcinoma

BackgroundThe response of advanced clear cell renal cell carcinoma (ccRCC) to immunotherapy is still not durable, suggesting that the immune landscape of ccRCC still needs to be refined, especially as some molecules that have synergistic effects with immune checkpoint genes need to be explored.MethodsThe expression levels of CENPM and its relationship with clinicopathological features were explored using the ccRCC dataset from TCGA and GEO databases. Quantitative polymerase chain reaction (qPCR) analysis was performed to validate the expression of CENPM in renal cancer cell lines. Kaplan-Meier analysis, COX regression analysis and Nomogram construction were used to systematically evaluate the prognostic potential of CENPM in ccRCC. Besides, single gene correlation analysis, protein–protein interaction (PPI) network, genetic ontology (GO), kyoto encyclopedia of genes and genomes (KEGG) and gene set enrichment analysis (GSEA) were used to predict the biological behaviour of CENPM and the possible signalling pathways involved. Finally, a comprehensive analysis of the crosstalk between CENPM and immune features in the tumor microenvironment was performed based on the ssGSEA algorithm, the tumor immune dysfunction and exclusion (TIDE) algorithm, the TIMER2.0 database and the TISIDB database.ResultsCENPM was significantly upregulated in ccRCC tissues and renal cancer cell lines and was closely associated with poor clinicopathological features and prognosis. Pathway enrichment analysis revealed that CENPM may be involved in the regulation of the cell cycle in ccRCC and may have some crosstalk with the immune microenvironment in tumors. The ssGSEA algorithm, CIBERSOPT algorithm suggests that CENPM is associated with suppressor immune cells in ccRCC such as regulatory T cells. The ssGSEA algorithm, CIBERSOPT algorithm suggests that CENPM is associated with suppressor immune cells in ccRCC such as regulatory T cells. Furthermore, the TISIDB database provides evidence that not only CENPM is positively associated with immune checkpoint genes such as CTLA4, PDCD1, LAG3, TIGIT, but also chemokines and receptors (such as CCL5, CXCL13, CXCR3, CXCR5) may be responsible for the malignant phenotype of CENPM in ccRCC. Meanwhile, predictions based on the TIDE algorithm support that patients with high CENPM expression have a worse response to immunotherapy.ConclusionsThe upregulation of CENPM in ccRCC predicts a poor clinical outcome, and this malignant phenotype may be associated with its exacerbation of the immunosuppressive state in the tumor microenvironment.