Factors In Tumor Microenvironment Research Articles

Interconversion of Cancer Cells and Induced Pluripotent Stem Cells.

Cancer cells, especially cancer stem cells (CSCs), share many molecular features with induced pluripotent stem cells (iPSCs) that enable the derivation of induced pluripotent cancer cells by reprogramming malignant cells. Conversely, normal iPSCs can be converted into cancer stem-like cells with the help of tumor microenvironment components and genetic manipulation. These CSC models can be utilized in oncogenic initiation and progression studies, understanding drug resistance, and developing novel therapeutic strategies. This review summarizes the role of pluripotency factors in the stemness, tumorigenicity, and therapeutic resistance of cancer cells. Different methods to obtain iPSC-derived CSC models are described with an emphasis on exposure-based approaches. Culture in cancer cell-conditioned media or cocultures with cancer cells can convert normal iPSCs into cancer stem-like cells, aiding the examination of processes of oncogenesis. We further explored the potential of reprogramming cancer cells into cancer-iPSCs for mechanistic studies and cancer dependencies. The contributions of genetic, epigenetic, and tumor microenvironment factors can be evaluated using these models. Overall, integrating iPSC technology into cancer stem cell research holds significant promise for advancing our knowledge of cancer biology and accelerating the development of innovative and tailored therapeutic interventions.

Unveiling the Role of Mechanical Microenvironment in Hepatocellular Carcinoma: Molecular Mechanisms and Implications for Therapeutic Strategies.

Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer deaths globally. More than 80% of HCC patients have a background of fibrosis or cirrhosis, which leads to changes in physical factors in tumor microenvironment (TME), such as increased stiffness, solid stress, fluid stresses and structural alterations in the extracellular matrix (ECM). In the past, the focus of cancer research has predominantly been on genetic and biochemical factors in the TME, and the critical role of physical factors has often been overlooked. Recent discoveries suggest these unique physical signals are converted into biochemical signals through a mechanotransduction process that influences the biological behavior of tumor cells and stromal cells. This process facilitates the occurrence and progression of tumors. This review delves into the alterations in the mechanical microenvironment during the progression of liver fibrosis to HCC, the signaling pathways activated by physical signals, and the effects on both tumor and mesenchymal stromal cells. Furthermore, this paper summarizes and discusses the therapeutic options for targeting the mechanical aspects of the TME, offering valuable insights for future research into novel therapeutic avenues against HCC and other solid tumors.

Plasticity and resistance of cancer stem cells as a challenge for innovative anticancer therapies - do we know enough to overcome this?

According to the CSC hypothesis, cancer stem cells are pivotal in initiating, developing, and causing cancer recurrence. Since the identification of CSCs in leukemia, breast cancer, glioblastoma, and colorectal cancer in the 1990s, researchers have actively investigated the origin and biology of CSCs. However, the CSC hypothesis and the role of these cells in tumor development model is still in debate. These cells exhibit distinct surface markers, are capable of self-renewal, demonstrate unrestricted proliferation, and display metabolic adaptation. CSC phenotypic plasticity and the capacity to EMT is strictly connected to the stemness state. CSCs show high resistance to chemotherapy, radiotherapy, and immunotherapy. The plasticity of CSCs is significantly influenced by tumor microenvironment factors, such as hypoxia. Targeting the genetic and epigenetic changes of cancer cells, together with interactions with the tumor microenvironment, presents promising avenues for therapeutic strategies. See also the Graphical abstract(Fig. 1).

Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma.

In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

Intratumor heterogeneity: models of malignancy emergence and evolution

Intratumor heterogeneity: models of malignancy emergence and evolution

Exosomal miR-182 derived from bone marrow mesenchymal stem cells drives carfilzomib resistance of multiple myeloma cells by targeting SOX6

BackgroundMultiple myeloma (MM) is a common hematological malignancy. Drug resistance remains to be a major clinical challenge in MM therapy. In this study, we aim to investigate the functional roles of bone marrow mesenchymal stem cells (BMSC)-derived exosomal miR-182 on the carfilzomib resistance of MM and its underlying mechanism.MethodsqRT-PCR and Western blot methods were utilized to confirm the gene or protein expressions. CCK-8 and transwell assays were performed to measure the capabilities of proliferation, migration, and invasion. The molecular interactions were validated through ChIP and Dual luciferase assay.ResultsOur findings indicated that miR-182 expression was upregulated in serum, BMSCs and BMSC-derived exosomes from MM patients. Hypoxia-inducible factor-1α (HIF-1α), a key transcriptional factor in tumor microenvironment, could boost miR-182 expression by directly binding to its promoter, thus favoring exosomal secretion. Moreover, exosomal miR-182 from BMSCs could be transferred to MM cells and was able to promote malignant proliferation, metastasis, and invasion, as well as decrease the sensitivity of MM cells against carfilzomib. Additionally, SOX6 was identified as a downstream target of miR-182 in MM cells, and its expression was negatively regulated by miR-182. Rescue experiments proved that loss of SOX6 in MM cells dramatically reversed the promoting roles of BMSC-secreted exosomal miR-182 on proliferation, metastasis, and carfilzomib resistance in MM cells.ConclusionCollectively, our findings indicated that exosomal miR-182 derived from BMSCs contributed to the metastasis and carfilzomib resistance of MM cells by targeting SOX6. This study sheds light on the pathogenesis of the BMSC-derived exosome containing miR-182 in the malignant behaviors of MM cells and carfzomib resistance.

CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1-positive regulator for tumor immune evasion.

Regulation of tumoral PD-L1 expression is critical to advancing our understanding of tumor immune evasion and the improvement of existing antitumor immunotherapies. Herein, we describe a CRISPR-based screening platform and identified ATXN3 as a positive regulator for PD-L1 transcription. TCGA database analysis revealed a positive correlation between ATXN3 and CD274 in more than 80% of human cancers. ATXN3-induced Pd-l1 transcription was promoted by tumor microenvironmental factors, including the inflammatory cytokine IFN-γ and hypoxia, through protection of their downstream transcription factors IRF1, STAT3, and HIF-2α. Moreover, ATXN3 functioned as a deubiquitinase of the AP-1 transcription factor JunB, indicating that ATNX3 promotes PD-L1 expression through multiple pathways. Targeted deletion of ATXN3 in cancer cells largely abolished IFN-γ- and hypoxia-induced PD-L1 expression and consequently enhanced antitumor immunity in mice, and these effects were partially reversed by PD-L1 reconstitution. Furthermore, tumoral ATXN3 suppression improved the preclinical efficacy of checkpoint blockade antitumor immunotherapy. Importantly, ATXN3 expression was increased in human lung adenocarcinoma and melanoma, and its levels were positively correlated with PD-L1 as well as its transcription factors IRF1 and HIF-2α. Collectively, our study identifies what we believe to be a previously unknown deubiquitinase, ATXN3, as a positive regulator for PD-L1 transcription and provides a rationale for targeting ATXN3 to sensitize checkpoint blockade antitumor immunotherapy.

Abstract B038: Targeting a Treg-specific deubiquitinase module for antitumor immune therapy

Abstract Checkpoint immunotherapies have transformed the treatment landscape for multiple human malignancies, but still with very limited success in treatment of many human cancers. A major hurdle is mediated by regulatory T (Treg) cells, which suppress the function of antitumor effector T cells. However, current approaches in targeting Treg to activate antitumor immune responses have shown only transient efficacy and are highly unspecific. Importantly, our recent studies, through unbiased CRISPR screening, identified the death from cancer cell signature gene USP22 required for optimal FoxP3 expression. USP22 genetic inhibition resulted in an approximately 15-25% reduction of FoxP3 expression in Tregs and partially diminishes Treg suppressive functions, which consequently results in elevated antitumor immunity against a broad spectrum of cancer types in mice. Therefore, a 20% reduction in FoxP3 protein expression, in this case, by USP22 inhibition, creates an ideal therapeutic window to boost antitumor immunity without triggering extensive autoimmune inflammatory responses (Nature, 2020). More recently, we further demonstrated that tumor microenvironment factors, including TGF-β, hypoxia, and tumor metabolites, induce Treg fitness/adaptation through selectively upregulating a deubiquitinase module, including USP21 and USP22 (Science Advances, 2022). Our ongoing study has identified USP22-specific small molecule inhibitors that largely diminish Treg fitness and dramatically inhibit tumor growth at a clinically relevant setting. In addition, our recent unpublished single-cell RNA-seq characterization revealed a novel function of the Treg-specific deubiquitination module in Treg terminal differentiation into a unique immune suppressive subpopulation, specifically in the tumor microenvironment. Collectively, our study defines a novel Treg deubiquitination module in tumor immunosurveillance and provides a rationale for the first Treg-specific targeting in antitumor immune therapy. Citation Format: Deyu Fang. Targeting a Treg-specific deubiquitinase module for antitumor immune therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B038.

Abstract A002: Analysis of tumor microenvironments in ovarian cancer patients receiving anti-BTN1A1 immunotherapy combined with standard-of-care therapy

Abstract Background Immune checkpoints have emerged as key regulators of the immune responses against various tumor types. Butyrophilin 1A1 (BTN1A1) has been identified as a novel immune checkpoint protein that has the potential to be targeted for new immunotherapeutic treatment options. We have observed that BTN1A1 and PD-L1 expression are mutually exclusive in various human solid tumors. Recently, Nelmastobart (BTN1A1-targeting antibody, hSTC810) has successfully completed phase 1 clinical trials. To ensure the effectiveness of Nelmastobart, it is crucial to possess a profound comprehension of patients’ tumor microenvironment factors involved. Here, we report Opal multiplex immunofluorescence and Hyperion imaging mass cytometry approach that includes a deeper understanding of the spatial relationships in the tumor microenvironment. Methods In a first-of-its-kind Phase 1 clinical trial, we are to characterize the safety profile and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Nelmastobart is administered as monotherapy at increasing dose levels of 0.3, 1, 3, 6, 10, and 15 mg/kg on a Q2W schedule. To understand the heterogeneity of the interaction mechanisms between immune cells and cancer cells, Patients’ FFPE specimens were stained cancer and immune cells using Opal multiplex immunofluorescence and analyzed Hyperion imaging mass cytometer. Results We enrolled 45 pts with various cancers in a phase I trial of anti-BTN1A1, a novel immunotherapy. We tested doses from 0.3 to 15 mg/kg and found no DLTs. We report results for ovarian cancer. Opal multiplex immunofluorescence analysis showed that anti-BTN1A1 therapy increased the infiltration and activation of CD8+ T cells and NK cells and decreased the level of regulatory T cells in the tumor microenvironment. We also found the opposite expression of BTN1A1 in PD-L1-expressing cancer cells in KI67-negative tumors from ovarian cancer patients. Conclusions Nelmastobart treatment activates immune response pathways and enhances anti-tumor activity with anti-PD-L1 combination therapy in vitro, in vivo, and clinical settings. The results of the study suggest that BTN1A1 is a novel immune checkpoint that can be targeted to overcome resistance to conventional therapies in cancer patients. Citation Format: Stephen S Yoo, Youngseung Kim, Seung Hoon Lee, Soohyeon Lee, Sangjoon Shin, Patricia LoRusso, Hyunjin Jung, David Hong. Analysis of tumor microenvironments in ovarian cancer patients receiving anti-BTN1A1 immunotherapy combined with standard-of-care therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A002.

North American Adult T-Cell Leukemia/Lymphoma Has Frequent Mutations in CCR4 and Responds in Vitro to a Small Molecule CCR4 Antagonist, CCR4-351

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive disease of malignant CD4+ T cells that develops in human T-lymphotropic virus-1 (HTLV-1) carriers. Patients diagnosed with ATLL have the worst survival among all peripheral T-cell lymphomas. There is an urgent need for in-depth understanding of its pathogenesis and development of new treatment strategies. We and others have shown that ATLLs diagnosed in the Japanese (J-ATLL) and North American (NA-ATLL) patients have differences in clinical characteristics and immune-genetic landscape. Among the most frequently mutated genes in J-ATLL cohorts is CCR4, a chemokine receptor that is targeted by C-terminal truncation mutations in one third of the cases. These mutations result in a more stabilized surface CCR4 and have been reported to cause elevated Akt activation following chemokine stimulation. Since our previous targeted exon sequencing study did not include CCR4, this work was initiated to assess CCR4 mutation frequency in NA-ATLL cases and to evaluate the preclinical activity of a small molecule CCR4 antagonist. This is because, although an anti-CCR4 mAb, mogamulizumab, has been approved in Japan to treat ATLL, this therapy failed in a Phase 2 trial among patients outside of Japan. Thus, mogamulizumab is not available as a routine treatment for NA-ATLL patients. We compiled CCR4 gene status data from bulk RNA-seq (n=10) and whole genome sequencing (WGS) analysis (n = 10). Out of a total of 17 NA-ATLL cases, 8 (47.1%) carried CCR4 gene alterations that included in-frame and frameshift indels, as well as nonsense mutations targeted to the C-terminus cytoplasmic tail and also the trans-membrane domain. In subtype analysis, 6 out 14 acute cases (42.9%) and 2 out of 3 (66.7%) of chronic cases carried at least one copy of mutated CCR4 gene, indicating that the mutation frequency in NA-ATLL is possibly even higher than that reported for the Japanese cohorts ( Figure 1). We then evaluated cell surface CCR4 expression using flow cytometry. The primary ATLL cells (CD4 +CD7 -CD8 -) from all 7 diagnostic samples uniformly express markedly increased levels of CCR4 relative to healthy control CD4 T cells. Interestingly, CCR4 expression among 8 ATLL cell lines is highly variable, implying that in vivo, tumor microenvironment factors may also contribute to sustained CCR4 upregulation in addition to the influence from the HTLV-1 oncoprotein, HBZ. FLX475 is an orally active small molecule CCR4 antagonist that is currently in a Phase 1/2 study (NCT03674567) in several types of advanced cancer including EBV+ NK/T cell lymphoma. So far, favorable clinical antitumor activity has been observed that includes complete responses with FLX475 monotherapy and encouraging combination activity (Lin C.-C. et al ESMO-IO 2022 Dec; #187P). Using several CCR4-positive cell lines, we examined in vitro anti-ATLL activity of CCR4-351, a CCR4 antagonist that is a highly related analog of FLX475. CCR4 is the exclusive homing receptor for two chemokine molecules, CCL17 and CCL22. In a transwell assay, both chemokines can elicit strong chemotaxis activity in a J-ATLL cell line ED40515(+). However, only CCL22 but not CCL17 can induce significant chemotaxis in two NA-ATLL cell lines, ATL#13 and ATL#29. The exact cause of this difference between these cell lines awaits future studies. In these transwell-based assays, CCR4-351 exhibited potent chemotaxis inhibitory activity with IC 50 values ranging from 7-60 nM ( Figure 2). In addition, when the cell lines were cultured under growth factor-deprivation conditions, CCR4-351 treatment caused a mild reduction in total cell viability, suggesting an additional anti-ATLL mechanism of action. In summary, in this first study of the CCR4 pathway status in NA-ATLL, we found that nearly half of the cases in our ATLL cohort carried a mutated CCR4 gene. Contrary to primary ATLL cells, ATLL cell lines exhibit a wide variation in CCR4 expression. CCL22 but not CCL17 induced strong chemotaxis behavior in NA-ATLL cell lines, which was potently inhibited by a small molecule CCR4 antagonist, CCR4-351. Since extramedullary presentation is frequently seen in NA-ATLL and central nervous system involvement is an adverse prognostic feature, inhibiting chemotaxis with a CCR4 antagonist such as FLX475 may be an effective therapeutic approach.

Loss of p53-DREAM-mediated repression of cell cycle genes as a driver of lymph node metastasis in head and neck cancer

BackgroundThe prognosis for patients with head and neck cancer (HNC) is poor and has improved little in recent decades, partially due to lack of therapeutic options. To identify effective therapeutic targets, we sought to identify molecular pathways that drive metastasis and HNC progression, through large-scale systematic analyses of transcriptomic data.MethodsWe performed meta-analysis across 29 gene expression studies including 2074 primary HNC biopsies to identify genes and transcriptional pathways associated with survival and lymph node metastasis (LNM). To understand the biological roles of these genes in HNC, we identified their associated cancer pathways, as well as the cell types that express them within HNC tumor microenvironments, by integrating single-cell RNA-seq and bulk RNA-seq from sorted cell populations.ResultsPatient survival-associated genes were heterogenous and included drivers of diverse tumor biological processes: these included tumor-intrinsic processes such as epithelial dedifferentiation and epithelial to mesenchymal transition, as well as tumor microenvironmental factors such as T cell-mediated immunity and cancer-associated fibroblast activity. Unexpectedly, LNM-associated genes were almost universally associated with epithelial dedifferentiation within malignant cells. Genes negatively associated with LNM consisted of regulators of squamous epithelial differentiation that are expressed within well-differentiated malignant cells, while those positively associated with LNM represented cell cycle regulators that are normally repressed by the p53-DREAM pathway. These pro-LNM genes are overexpressed in proliferating malignant cells of TP53 mutated and HPV + ve HNCs and are strongly associated with stemness, suggesting that they represent markers of pre-metastatic cancer stem-like cells. LNM-associated genes are deregulated in high-grade oral precancerous lesions, and deregulated further in primary HNCs with advancing tumor grade and deregulated further still in lymph node metastases.ConclusionsIn HNC, patient survival is affected by multiple biological processes and is strongly influenced by the tumor immune and stromal microenvironments. In contrast, LNM appears to be driven primarily by malignant cell plasticity, characterized by epithelial dedifferentiation coupled with EMT-independent proliferation and stemness. Our findings postulate that LNM is initially caused by loss of p53-DREAM-mediated repression of cell cycle genes during early tumorigenesis.

TMIC-82. SPATIAL AND SINGLE-CELL PROTEOMIC LANDSCAPING OF THE HYPOXIC MICROENVIRONMENT IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is a fatal adult solid tumour with median overall survival of 18-20 months post-diagnosis; contributing factors to therapeutic inefficacy include acquisition of genomic alterations post-therapy, immune evasion, deregulated hypervascularization, and tumor microenvironmental factors such as hypoxia. Combined with extensive inter- and intra-tumoral heterogeneity at bulk and single-cell level, hypoxia contributes to a gradient of molecular alterations that are specific to different cell populations that make up tumour bulk and reside in specific niches. Hitherto, high-dimensional histopathologic analyses of hypoxic regions within GBM tissue have not been performed. We took a combined spatial and single-cell proteomic profiling approach to investigate the histopathologic features of hypoxia by leveraging a unique clinical study wherein the exogenous hypoxia marker, pimonidazole (PIMO), was administered to GBM-patients preoperatively. Tissue specimens were subjected to imaging mass cytometry, high-resolution imaging, and serial immunohistochemistry using a panel of markers associated with cellular hallmarks of hypoxia, metabolism, proliferation, stemness, angiogenesis, and immune cell types. Our findings showed that PIMO staining is associated with histopathologic features of hypoxia and correlates with specific metabolic, immune, and stemness markers in GBM; specific lymphocyte populations were depleted from hypoxic regions alongside alterations in macrophagic and microglial landscape in a niche-specific manner; hypoxia reduced the proportion of proliferating glioma initiating cells and altered the proliferative, transcriptional, and translational capacity of different cell populations; microvessel density was reduced in hypoxic microenvironment. Cytometry by time-of-flight further validated the altered proportions of specific immune cell types enriched in hypoxic populations of GBM microenvironment. Our study is the first to report use of PIMO to interrogate spatial, single-cell, and phenotypic architecture associated with tissue hypoxia and altered expression of biomarkers associated with hypoxia/glycolysis, immune infiltration, proliferation, and stemness. Identification of targetable biomarkers and mediators of hypoxia-driven habitats in GBM may provide direction for future immunotherapeutic research.

TMET-12. CDKN2A DELETION REMODELS LIPID METABOLISM TO PRIME GLIOBLASTOMA FOR FERROPTOSIS

Abstract Glioblastomas (GBM) are universally lethal brain tumors that exhibit extensive genetic and transcriptional heterogeneity. GBMs acquire metabolic adaptations in response to a multitude of intrinsic (oncogenotype) and extrinsic (tumor microenvironment) factors to fuel neoplastic progression. Large-scale multi-omic studies in cancer cell lines have further advanced our understanding of the intersection between molecular diversity and metabolic heterogeneity, indicating distinct metabolic vulnerabilities may exist within defined molecular subsets of cancer. However, the translatability of these observations into effective cancer therapies remains limited due to gaps in our understanding of the physiologic fidelity of metabolic studies conducted only in vitro. Thus, accounting for both the molecular diversity and environment of human tumors is crucial to identify translatable metabolic targets.

Involving stemness factors to improve CAR T-cell-based cancer immunotherapy.

Treatment with chimeric antigen receptor (CAR) T cells indicated remarkable clinical responses with liquid cancers such as hematological malignancies; however, their therapeutic efficacy faced with many challenges in solid tumors due to severe toxicities, antigen evasion, restricted and limited tumor tissue trafficking and infiltration, and, more importantly, immunosuppressive tumor microenvironment (TME) factors that impair the CAR T-cell function adds support survival of cancer stem cells (CSCs), responsible for tumor recurrence and resistance to current cancer therapies. Therefore, in-depth identification of TME and development of more potent CAR platform targeting CSCs may overcome the raised challenges, as presented in this review. We also discuss recent stemness-based innovations in CAR T-cell production and engineering to improve their efficacy in vivo, and finally, we propose solutions and strategies such as oncolytic virus-based therapy and combination therapy to revive the function of CAR T-cell therapy, especially in TME of solid tumors in future.

A CaCO3-based nanoplatform with sonodynamic and tumor microenvironment activated for combined in vitro cancer therapy

IntroductionSonodynamic therapy (SDT) has potential clinical applications for cancer therapy, and is yet restricted by complex tumor microenvironmental (TME) factors. Thus, the research problem of TME modulation as well as efficient tumor treatment still needs to be clarified. MethodIn this study, a calcium carbonate (CaCO3) nanoplatform was designed for ultrasound (US) and TME response-triggered, which encapsulated Ag2S and loaded with l-Arg, and further wrapped with RBC/Platelet membrane, named as QD@Ca/ML-Arg. ResultsNon-invasive US-triggered SDT by Ag2S and acidic environment-responsive drug release were achieved. In vitro experiments validated the efficacy of SDT, Ca-ion interference and nitric oxide (NO) gas therapy as combined therapy for cancer treatment. By means of RNA sequencing, the cancer therapeutic mechanism of SDT in redox-related pathways was elucidated. The immunosuppressive TME was simulated with a M2-macrophage/cancer cell co-culture system to confirm the immune activating effect of immunogenic cell death (ICD). ConclusionAccordingly, the potential of QD@Ca/ML-Arg-was demonstrated for in vitro TME modulation, cancer therapeutic efficacy and clinical translation.

Resistance to immune checkpoint inhibitors in the treatment of metastatic renal cancer

Over the past 5 years, checkpoint inhibitors including anti-CTLA-4 and anti-PD-1/PD-L1 blockers have changed approaches to therapy of metastatic renal cell cancer. However, more than 55 % of patients with advanced kidney cancer remain resistant to immunotherapy. This paper refects the causes that lead to primary and acquired resistance to immune checkpoint inhibitors during the treatment of metastatic renal cell cancer. The purpose of the study was to elucidate the mechanisms underlying resistance to checkpoint inhibitors during the treatment of metastatic kidney cancer. Material and Methods. A literature search was conducted using Pubmed database in the time interval between 2010 and 2023. We identifed 286 publications of which 59 were relevant for our review. Results. There are many factors that contribute to primary or acquired resistance to immunotherapy, including factors associated with the tumor cell as well as tumor microenvironment factors. Conclusion. Many innovative approaches to overcoming resistance to monoclonal antibodies are being investigated in clinical trials. In connection with the advent of new methods, the cellular composition of the tumor microenvironment and its role in the emergence of tumor resistance to immunotherapy are becoming increasingly clear. New biomarkers are emerging to help identify the best candidates for immunotherapy in metastatic kidney cancer. However, they require further study.

High expression of NOLC1 as an independent prognostic factor for survival in patients with colorectal cancer

BackgroundAs a phosphorylated protein, NOLC1 is mainly located in the nucleus and is highly expressed in a variety of tumors, participating in the regulation of cell proliferation and aging. This study further investigated the role of NOLC1 in colorectal cancer tumors, aiming to provide sufficient scientific evidence for the clinical treatment of colorectal cancer.MethodsWe used TCGA, GEO, TNMplot, GEPIA, and other databases to explore the expression level of NOLC1 in colorectal cancer patients, as well as the correlation between the clinical characteristics of colorectal cancer patients and their expression, and conducted the prognostic analysis. Immunohistofluorescence (IHF) staining verified the analytical results. Subsequently, KEGG and GO enrichment analysis was used to identify the potential molecular mechanism of NOLC1 promoting the occurrence and development of colorectal cancer. The influence of NOLC1 expression on the immune microenvironment of colorectal cancer patients was further investigated using the TIMER database. GDSC database analysis was used to screen out possible anti-colorectal cancer drugs against NOLC1. Finally, we demonstrated the effect of NOLC1 on the activity and migration of colorectal cancer cells by Edu Cell proliferation assay and Wound Healing assay in vitro.ResultsOur results suggest that NOLC1 is overexpressed in colorectal cancer, and that overexpression of NOLC1 is associated with relevant clinical features. NOLC1, as an independent risk factor affecting the prognosis of colorectal cancer patients, can lead to a poor prognosis of colorectal cancer. In addition, NOLC1 may be associated with MCM10, HELLS, NOC3L, and other genes through participating in Wnt signaling pathways and jointly regulate the occurrence and development of colorectal cancer under the influence of the tumor microenvironment and many other influencing factors. Related to NOLC1: Selumetinib, Imatinib, and targeted drugs such as Lapatinib have potential value in the clinical application of colorectal cancer. NOLC1 enhances the proliferation and migration of colorectal cancer cells.ConclusionsHigh expression of NOLC1 as an independent prognostic factor for survival in patients with colorectal cancer. NOLC1 enhances the proliferation and migration of colorectal cancer cells. Further studies and clinical trials are needed to confirm the role of NOLC1 in the development and progression of colorectal cancer.

Transcription factor Zhx2 is a checkpoint that programs macrophage polarization and antitumor response.

Macrophages are usually educated to tumor-associated macrophages (TAMs) in cancer with pro-tumor functions by tumor microenvironment (TME) and TAM reprogramming has been proposed as a potential tumor immunotherapy strategy. We recently demonstrated the critical role of Zinc-fingers and homeoboxes 2 (Zhx2) in macrophages' metabolic programming. However, whether Zhx2 is responsible for macrophage polarization and TAMs reprogramming is largely unknown. Here, we show that Zhx2 controls macrophage polarization under the inflammatory stimulus and TME. Myeloid-specific deletion of Zhx2 suppresses LPS-induced proinflammatory polarization but promotes IL-4 and TME-induced anti-inflammatory and pro-tumoral phenotypes in murine liver tumor models. Factors in TME, especially lactate, markedly decrease the expression of Zhx2 in TAMs, leading to the switch of TAMs to pro-tumor phenotype and consequent cancer progression. Notably, reduced ZHX2 expression in TAM correlates with poor survival of HCC patients. Mechanistic studies reveal that Zhx2 associates with NF-κB p65 and binds to the Irf1 promoter, leading to transcriptional activation of Irf1 in macrophages. Zhx2 functions in maintaining macrophage polarization by regulating Irf1 transcription, which may be a potential target for macrophage-based cancer immunotherapy.

Environmental Determinants of Ferroptosis in Cancer.

Given the enormous suffering and death associated with human cancers, there is an urgent need for novel therapeutic approaches to target tumor growth and metastasis. While initial efforts have focused on the dysregulated oncogenic program of cancer cells, recent focus has been on the modulation and targeting of many "cancer-friendly," non-genetic tumor microenvironmental factors, which support and enable tumor progression and metastasis. Two prominent examples are anti-angiogenesis and immunotherapy that target tumor-supporting vascularization and the immune-suppressive tumor microenvironment (TME), respectively. Lately, there has been significant interest in the therapeutic potential of ferroptosis, a natural tumor suppression mechanism that normally occurs as a result of oxidative stress, iron imbalance, and accumulation of lipid peroxides. While numerous studies have identified various cell intrinsic mechanisms to protect or promote ferroptosis, the role of various TME stress factors are also recently recognized to modulate the tumor cells' susceptibility to ferroptosis. This review aims to compile and highlight evidence of these factors, how various TME stresses affect ferroptosis, and their implications in various stages of tumor development and expected response to ferroptosis-triggering therapeutics under development. Consequently, understanding ways to enhance ferroptosis sensitivity both intracellularly and in the TME may optimize therapeutic sensitivity to minimize or prevent tumor growth and metastasis.

Stromal Tumor-Infiltrating Lymphocytes Associated with Immunohistopathology and Molecular Subtypes of Breast Cancer in Vietnam.

Breast cancer is a heterogeneous disease with varied symptoms and pathogenesis, as well as variable prognosis and therapeutic outcomes. Stromal tumor-infiltrating lymphocytes, one of the tumor microenvironment factors, has been recognized as an important immunological biomarker that reflected the antitumor immune response in breast cancer. We analyzed 207 invasive breast cancer patients who had lumpectomy or mastectomy and have not received any pre-operative treatment. Clinicopathological characteristics, immunohistochemistry characteristics, molecular subtypes classification and stromal TILs evaluation were investigated. Stromal TILs correlated with well-established prognostic markers. Tumor grade showed significantly higher sTILs percentages in high-grade tumors than in low-grade tumors (p<0.001). There was a statistically significant association between intermediate and high levels of sTILs and a high Ki-67 index (p< 0.001). ER/PR negative was significantly related to high sTILs. Mean sTILs score was significantly higher in TNBC (40.1±31.6%) compared to others, statistically significant (p<0.001). In HER2-negative breast cancer, sTILs were significantly associated with histologic grade, ER status, PR status, and Ki67 index. sTILs played an important role, associated with unfavorable factors in breast cancer. Our findings support the use of stromal sTILs to identify a more aggressive phenotype of tumors.