Tumor Immune Response Research Articles

Advances in Immunotherapy and Targeted Therapy of Malignant Melanoma

Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes. Its mortality rate accounts for 90% of all dermatologic tumor mortality. Traditional treatments such as surgery, chemotherapy, and radiotherapy are unable to achieve the expected results due to MM’s low sensitivity, high drug resistance, and toxic side effects. As treatment advances, immunotherapy and targeted therapy have made significant breakthroughs in the treatment of MM and have demonstrated promising application prospects. However, the heterogeneity of tumor immune response causes more than half of patients to not benefit from clinical immunotherapy and targeted therapy, which delays the patient’s condition and causes them to suffer adverse immune events’ side effects. The combination of immunotherapy and targeted therapy can help improve therapeutic effects, delay drug resistance, and mitigate adverse effects. This review provides a comprehensive overview of the current development status and research progress of immune checkpoints, targeted genes, and their inhibitors, with a view to providing a reference for the clinical treatment of MM.

An epigenetic pathway regulates MHC-II expression and function in B cell lymphoma models.

Mutations or homozygous deletions of MHC class II (MHC-II) genes are commonly found in B cell lymphomas that develop in immune-privileged sites and have been associated with patient survival. However, the mechanisms regulating MHC-II expression, particularly through genetic and epigenetic factors, are not yet fully understood. In this study, we identified a key signaling pathway involving the histone H2AK119 deubiquitinase BRCA1 associated protein 1 (BAP1), the interferon regulatory factor interferon regulatory factor 1 (IRF1), and the MHC-II transactivator class II transactivator (CIITA), which directly activates MHC-II gene expression. Disruption of the BAP1/IRF1/CIITA axis leads to a functional attenuation of MHC-II expression and MHC-II-dependent immune cell infiltration, leading to accelerated tumor growth in immunocompetent mice. Additionally, we demonstrated that pharmacological inhibition of polycomb repressive complex 1 (PRC1) - which deposits histone H2K119Ub and opposes BAP1 activity - can restore MHC-II gene expression in BAP1-deficient B cell lymphoma cells. These findings suggest that BAP1 may function as a tumor suppressor by regulating the tumor microenvironment and immune response. Our study also establishes the rationale for therapeutic strategies to restore tumor-specific MHC-II expression and enhance immunotherapy outcomes at epigenetic levels in B cell lymphoma treatment.

Identification of Immune Infiltration-Associated CC Motif Chemokine Ligands as Biomarkers and Targets for Colorectal Cancer Prevention and Immunotherapy

Colorectal cancer (CRC) is the third most common cancer globally, with limited effective biomarkers and sensitive therapeutic targets. An increasing number of studies have highlighted the critical role of tumor microenvironment (TME) imbalances, particularly immune escape due to impaired chemokine-mediated trafficking, in tumorigenesis and progression. Notably, CC chemokines (CCLs) have been shown to either promote or inhibit angiogenesis, metastasis, and immune responses in tumors, thereby influencing cancer development and patient outcomes. However, the diagnostic and prognostic significance of CCLs in CRC remains unclear. In this study, multiple online tools for bioinformatics analyses were utilized. The findings revealed that the mRNA expression levels of CCL3, CCL4, and CCL26 were significantly elevated in CRC tissues compared to normal tissues, whereas CCL2, CCL5, CCL11, CCL21, and CCL28 mRNA levels were markedly downregulated. Additionally, dysregulation of CCL4, CCL5, and CCL21 was strongly associated with clinical staging, and elevated levels of CCL4, CCL11, and CCL28 were linked to significantly prolonged survival in CRC patients. Functional enrichment analysis indicated that the cellular roles of CCLs were predominantly associated with the chemokine, Wnt, and Toll-like receptor signaling pathways, as well as protein kinase activity. Furthermore, transcriptional regulation of most CCLs involved RELA and NFKB1. Key downstream targets included members of the SRC family of tyrosine kinases (HCK, LYN, and LCK), serine/threonine kinases (ATR and ATM), and others such as CSNK1G2, NEK2, and CDK2. Moreover, CCLs (CCL2, CCL3, CCL4, CCL5, CCL11, CCL21, and CCL28) exhibited strong correlations with major infiltration-related immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. In conclusion, our study provides novel insights into the potential utility of CCLs as biomarkers and therapeutic targets for CRC prevention and immunotherapy.

SMR-guided molecular subtyping and machine learning model reveals novel prognostic biomarkers and therapeutic targets in non-small cell lung adenocarcinoma

Non-small cell lung adenocarcinoma (LUAD) is a markedly heterogeneous disease, with its underlying molecular mechanisms and prognosis prediction presenting ongoing challenges. In this study, we integrated data from multiple public datasets, including TCGA, GSE31210, and GSE13213, encompassing a total of 867 tumor samples. By employing Mendelian randomization (MR) analysis, machine learning techniques, and comprehensive bioinformatics approaches, we conducted an in-depth investigation into the molecular characteristics, prognostic markers, and potential therapeutic targets of LUAD. Our analysis identified 321 genes significantly associated with LUAD, with CENP-A, MCM7, and DLGAP5 emerging as highly connected nodes in network analyses. By performing correlation analysis and Cox regression analysis, we identified 26 prognostic genes and classified LUAD samples into two molecular subtypes with significantly distinct survival outcomes. The Random Survival Forest (RSF) model exhibited robust prognostic predictive capabilities across multiple independent cohorts (AUC > 0.75). Beyond merely predicting patient outcomes, this model also captures key features of the tumor immune microenvironment and potential therapeutic responses. Functional enrichment analysis revealed the complex interplay of cell cycle regulation, DNA repair, immune response, and metabolic reprogramming in the progression of LUAD. Furthermore, we observed a strong correlation between risk scores and the expression of specific cytokines, such as CCL17, CCR2, and CCL20, suggesting novel avenues for developing cytokine network-based therapeutic strategies. This study offers fresh insights into the molecular subtyping, prognostic prediction, and personalized therapeutic decision-making in LUAD, laying a critical foundation for future clinical applications and targeted therapy research.

Tumour Mutational Burden and Immune Checkpoint Inhibitor Response in Non-small Cell Lung Cancer: A Continuous Modelling Approach.

Tumour mutational burden (TMB) is an established biomarker for patients treated with immune checkpoint inhibitors (ICIs). The optimal TMB cut-off is uncertain. It is also uncertain whether there is a sharp TMB threshold or a more graduated change in clinical outcomes as TMB increases. We aimed to determine the relationship between TMB and ICI treatment outcomes using alternative statistical approaches in patients with non-small cell lung cancer. Tumour mutational burden was evaluated as a prognostic and predictive biomarker in advanced non-small cell lung cancer utilising data from two real-world cohorts of ICI use (n = 968) and three randomised controlled trials evaluating ICIs (n = 1588). The non-linear relationship between continuous TMB and response/survival/efficacy outcomes was evaluated using statistical methods that do not require specifying a TMB cut-off. Median TMB for all cohorts was seven mutations/megabase, excluding MYSTIC, where the median was 13 mutations/megabase. Progressively higher TMB was significantly associated with a progressively higher objective response rate and progression-free survival in ICI-treated patients in Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] (objective response rate: p < 0.001, progression-free survival: p < 0.001), Strata Clinical Molecular Database [SCMD] (progression-free survival: p = 0.023) and OAK/POPLAR (objective response rate: p = 0.017, progression-free survival: p < 0.001) This relationship was not apparent for patients treated with chemotherapy. There was no obvious TMB threshold for ICI response. The relationship between TMB and overall survival was more complex and heterogeneous. Using a single cut-off to analyse a continuous biomarker may hide important information. Methods that provide more nuance to the underlying relationship between TMB and outcomes enable readers to judge for themselves the value and limitations of TMB cut-offs proposed for clinical practice.

Genomic Profiling of Intimal Sarcoma Reveals Molecular Subtypes with Distinct Tumor Microenvironments and Therapeutic Implications

Intimal sarcoma is a rare and aggressive soft-tissue sarcoma with limited treatment options. We explored genomic profiles of intimal sarcoma to uncover therapeutic implications. We analyzed tumor tissues from patients with intimal sarcoma who visited the Seoul National University Hospital (SNUH) using whole-exome, whole-transcriptome, and clinical next-generation sequencing (NGS), integrated with intimal sarcoma NGS data from two public cohorts. We examined expression characteristics and tumor-infiltrating lymphocytes (TILs) according to molecular subtypes. Our study included 42 samples in total. Thirty-three patients showing copy number variation (CNV) enrichment with frequent CDK4/MDM2 amplifications were classified as the CNV-high (CNV-H) subtype. Five patients showing predominant MLH1 mutations or homozygous deletions were classified as the microsatellite instability-high-like (MSI-H-like) subtype. Hallmark pathways up-regulated in the CNV-H subtype included Wnt β-catenin and Hedgehog signaling. In the MSI-H-like subtype, interferon-γ response, tumor necrosis factor-α signaling via nuclear factor-κB, interferon-α response, inflammatory response, and interleukin-6-Jak-Stat3 signaling were up-regulated. CNV-H subtype samples predominantly showed an immune-desert phenotype, whereas MSI-H-like subtype samples predominantly showed an immune-inflamed phenotype. Two MSI-H-like subtype patients received pembrolizumab and experienced tumor shrinkage. We identified two intimal sarcoma molecular subtypes. Compared with CNV-H, MSI-H-like is enriched in pathways associated with tumor immune responses and TILs. Further efforts and clinical trials to better define these molecular subtypes are warranted to open new avenues for personalized treatment approaches and improve patient outcomes.

Magnetically driven bionic nanorobots enhance chemotherapeutic efficacy and the tumor immune response via precise targeting

Magnetically driven bionic nanorobots enhance chemotherapeutic efficacy and the tumor immune response via precise targeting

Enhanced antitumor immunity in breast cancer: Synergistic effects of ADAM10/ADAM17 inhibition, metabolic modulation, and camptothecin-loaded selenium nanoparticles.

In this study, we investigate the impact of a multi-targeted therapeutic approach that includes camptothecin (CPT), a potent chemotherapeutic topoisomerase inhibitor; metformin (Met), a metabolic modulator with emerging anti-tumor effects; and GW280264X, an inhibitor of ADAM 10/ADAM 17 enzymes, which are associated with tumor invasion and immune response. The study aims to assess the combined effects of these agents in enhancing CD8+ T cell-mediated anti-tumor immunity and suppressing cancer cell growth in triple-negative breast cancer (TNBC) models, both in vitro and in vivo. Cell viability was performed on the 4T1 human TNBC cell line. Furthermore, we examined c-MYC protein expression by western blot, TOX and NR4A expression by Real-time PCR, and the number of CD8+ CD28+ T cells by immunofluorescence assay to demonstrate the anticancer effects of combined of CPT, Met and GW280264X in BC growth, exhaustion and senescence of T cells. Regarding cell viability, HA-Se@CPT+Met and HA-Se@CPT+Met+GW280264X treatments decreased 4T1 cell growth (p<0.001). Combination therapy of Met, HA-Se@CPT, and GW280264X significantly reduced tumor volume and weight in vivo. This treatment also increased the number of CD8+ CD28+ T cells in the tumor microenvironment (TME) of BC (p<0.0001) and decreased the expression of TOX and NR4A (p<0.0001, p<0.01). Furthermore, decreased expression of c-MYC as an oncogene protein was seen in the single and combined treatment by HA-Se@CPT and GW280264X (p<0.05). These findings suggest that of HA-Se@CPT, Met, and GW280264X may inhibit tumor progression in BC by improving the function and infiltration of CD8+ T cells. Their effect is more pronounced when used in combination.

MAF1 inhibits hepatocarcinogenesis by fostering an immunostimulatory tumor microenvironment

BackgroundThe biological significance of MAF1, a tumor suppressor, in carcinogenesis and immune response of hepatocellular carcinoma (HCC) remains unreported. Understanding the underlying mechanisms by which MAF1 enhances anti-tumor immunity in...

Liposomes-mediated enhanced antitumor effect of docetaxel with BRD4-PROTAC as synergist for breast cancer chemotherapy/immunotherapy.

It has been reported that proteolysis-targeting chimeras (PROTACs) can effectively degrade intracellular oncogenic proteins, providing an ideal strategy for cancer treatment. ARV825, a bromodomain-containing protein 4 (BRD4)-PROTAC, has demonstrated the capacity to enhance the antitumor effect of the classic chemotherapeutic agent docetaxel (DTX). However, there are three major challenges to the broader in vivo application of ARV825: poor solubility, poor permeability, and off-target effects. Additionally, the efficient co-delivery of ARV825 and DTX to tumor tissues for a synergistic therapeutic effect remains unresolved. In this study, liposomes were utilized as co-delivery vehicles for ARV825 and DTX to effectively address these issues. The well-established liposomes significantly improved the solubility of both ARV825 and DTX while maintaining a sustained release profile in blood-mimetic conditions. The co-loaded liposomes accumulated in tumor tissues via the enhanced permeability and retention (EPR) effect. After internalization, ARV825 effectively degraded intracellular BRD4 proteins and downregulated the expression of both Bcl-2 and PD-L1 proteins, thereby increasing tumor cell apoptosis and enhancing the tumor immune response. This, in turn, augmented the antitumor effect of DTX in vivo without undesired side effects. In conclusion, BRD4-PROTAC may serve as a promising synergistic agent alongside the conventional chemotherapeutic agent DTX, with liposomes functioning as effective co-delivery vehicles.

Multiomics integration and machine learning reveal prognostic programmed cell death signatures in gastric cancer

Gastric cancer (GC) is characterized by notable heterogeneity and the impact of molecular subtypes on treatment and prognosis. The role of programmed cell death (PCD) in cellular processes is critical, yet its specific function in GC is underexplored. This study applied multiomics approaches, integrating transcriptomic, epigenetic, and somatic mutation data, with consensus clustering algorithms to classify GC molecular subtypes and assess their biological and immunological features. A machine learning model was developed to create the Gastric Cancer Multi-Omics Programmed Cell Death Signature (GMPS), targeting PCD-related genes. We verified the expression of the GMPS hub genes using the RT-qPCR method. The prognostic influence of GMPS on GC was then evaluated. Single-cell analysis was performed to examine the heterogeneity of PCD characteristics in GC. Findings indicate that GMPS notably correlates with patient survival rates, tumor mutational burden (TMB), and copy number variations (CNV), demonstrating substantial prognostic predictive power. Moreover, GMPS is closely associated with the tumor microenvironment (TME) and immune therapy response. This research elucidates the molecular subtypes of GC, highlighting PCD’s critical role in prognosis assessment. The relationship between GMPS and immune therapy response, alongside gastric cancer’s microenvironmental features, provides insights for personalized treatment.

Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment

Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (telomeric repeat binding factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the IL1R1 promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like IL6, IL8, and TNF. Further, IL1R1 expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with IL1R1 expression. The use of both IL1 Receptor antagonist (IL1RA) and IL1R1 targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (&gt;90 patients), tumour-derived organoids, cancer cells, and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.

Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment.

Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (telomeric repeat binding factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the IL1R1 promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like IL6, IL8, and TNF. Further, IL1R1 expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with IL1R1 expression. The use of both IL1 Receptor antagonist (IL1RA) and IL1R1 targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (>90 patients), tumour-derived organoids, cancer cells, and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.

Pan‐Cancer Analysis of Ezrin: A Comprehensive Examination of Its Prognostic Value and Immunological Implications

ABSTRACTBackgroundEzrin, a member of the ERM protein family, has emerged as a pivotal player in the progression of diverse tumor types and exhibits substantial immunomodulatory capabilities in inflammatory disorders and tumor‐associated immune reactions. Studies have validated the antitumor efficacy of ezrin inhibitors. However, a comprehensive pan‐cancer analysis to fully elucidate the functional implications of ezrin has not been performed.MethodsHerein, we performed a multifaceted database investigation to evaluate ezrin expression patterns in relation to clinical outcomes, immune checkpoint modulators, prognostic indicators, genomic profiles, and immunological features.ResultsOur analysis revealed distinct ezrin expression patterns across various cancers, with a pronounced association between ezrin expression and immune cell infiltration. Furthermore, drug sensitivity assessments using the GDSC and CTRP databases underscored a robust correlation between ezrin expression and responsiveness to anticancer agents, highlighting its potential as a therapeutic target. Notably, ezrin expression also correlated with patient survival outcomes in the context of anti‐PD1 therapy treatment, suggesting its potential role as a predictive biomarker for immune checkpoint blockade therapies.ConclusionOur results indicate ezrin as a promising immunomodulatory target and a valuable diagnostic and prognostic marker for select cancer types. However, the intricate mechanisms underlying ezrin involvement in tumor immune responses necessitate further in‐depth investigation to fully harness its therapeutic and prognostic potential.

Prediction of prognosis, immunogenicity and efficacy of immunotherapy based on cholesterol metabolism in gastric cancer.

Cholesterol metabolism plays a crucial role in tumor progression and immune response modulation. However, the precise connection between cholesterol metabolism-related genes (CMRGs) and their implications for clinical prognosis, the tumor microenvironment (TME), and the outcomes of immunotherapy in gastric cancer remains to be fully elucidated. Transcriptome data and related clinical information from 675 gastric cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A total of 50 cholesterol metabolism-related genes (CMRGs) were identified from the Kyoto Encyclopedia of Genes and Genomes (KEGG, hsa04979). Consensus clustering analysis was used to classify patients into distinct molecular subgroups, while principal component analysis (PCA) was applied to develop a prognostic scoring system for predicting survival and immunotherapy response. The scoring system was validated using three independent cohorts of gastric cancer patients. Based on 49 CMRGs, 675 gastric cancer patients were categorized into three distinct subgroups with varying prognoses, tumor microenvironment features, and clinical characteristics. Further differential gene analysis and consensus clustering identified two additional subgroups. The prognostic scoring system developed through PCA demonstrated that the high-score subgroup had significantly improved survival, higher tumor mutational burden (TMB), and microsatellite instability (MSI), as well as a greater number of mutated genes, indicating greater sensitivity to immunotherapy. This system was validated in a real-world cohort undergoing immunotherapy. Additionally, the correlation between GPC3 expression and cholesterol levels was confirmed, highlighting GPC3's potential biological role. This study highlights the importance of CMRGs in gastric cancer, deepens our understanding of the tumor immune microenvironment, and guides individualized immunotherapy.

Are Probiotics Beneficial or Harmful for Pancreatic Cancer Outcomes?

Pancreatic cancer is influenced by interactions between cancer cells and the tumor microenvironment (TME), including tumor-infiltrating lymphocytes (TILs). Specifically, CD8 + T cells impact prognosis by eliminating cancer cells. Recent studies have revealed that microbiomes are present in pancreatic tissues and may affect tumor growth and immune responses. Additionally, recent studies revealed that the abundance of Bacteroides, Lactobacillus, and Peptoniphilus are associated with poor pancreatic cancer prognosis. This study investigates the role of oral probiotics in influencing pancreatic cancer outcomes. We retrospectively reviewed patients aged ≥ 18 years with pathologically confirmed pancreatic cancer from Seoul National University Hospital between January 2011 and January 2023. We investigated progression-free survival and overall survival between the control group and the probiotics group. Among pancreatic cancer patients undergoing palliative chemotherapy without radiotherapy and resection, there was a significant difference in overall survival (OS) when comparing the control group to the probiotics group (median: 10 months (9-11) vs. 12 months (9-19), p = 0.026). Regardless of the type of probiotics, oral probiotics may have a positive impact, but further research is still needed to understand the underlying immunological mechanisms.

Gut virome dysbiosis impairs antitumor immunity and reduces 5-fluorouracil treatment efficacy for colorectal cancer.

Despite the established influence of gut bacteria, the role of the gut virome in modulating colorectal cancer (CRC) patient chemotherapy response remains poorly understood. In this study, we investigated the impact of antiviral (AV) drug-induced gut virome dysbiosis on the efficacy of 5-FU in CRC treatment. Using a subcutaneous CRC mouse model, we assessed tumor growth and immune responses following AV treatment, fecal microbiota transplantation (FMT), and 5-FU administration. AV therapy reduced the abundance of gut DNA and RNA viruses, leading to accelerated tumor growth, shortened survival, and diminished chemotherapy efficacy. FMT restored the gut virome, improving tumor suppression and extending the survival of 5-FU-treated mice. Metagenomic sequencing revealed significant changes in virome composition, AV treatment expanded Kahnovirus, Petivirales, and Enterogokushovirus, whereas FMT enriched Peduovirus STYP1, Mahlunavirus rarus, and Jouyvirus ev207. AV treatment reduced the number of dendritic cells and CD8+ T cells in peripheral blood and tumor tissues, impairing antitumor immunity, FMT reversed these deficiencies. To further investigate the underlying mechanisms, we examined the TLR3-IRF3-IFN-β pathway, essential for recognizing viral RNA and triggering immune responses. AV treatment downregulated this pathway, impairing immune cell recruitment and reducing chemotherapy efficacy, while activation of TLR3 with Poly(I:C) restored pathway function and enhanced the effectiveness of 5-FU. These findings suggest the importance of maintaining gut virome integrity or activating TLR3 as adjunct strategies to enhance chemotherapy outcomes in CRC patients.

Radiotherapy-resistant prostate cancer cells escape immune checkpoint blockade through the senescence-related ataxia telangiectasia and Rad3-related protein.

The majority of patients with prostate cancer (PCa) exhibit intrinsic resistance to immune checkpoint blockade (ICB) following radiotherapy (RT). This resistance is generally attributed to the limited antigen presentation of heterogeneous cells within tumors. Here, we aimed to isolate and characterize these diverse subgroups of tumor post-RT to understand the molecular mechanisms of their resistance to ICB. Single-cell RNA-sequencing (scRNA-seq) was used to profile senescent cancer cell clusters induced by RT in LNCaP cells. The expression and phosphorylation levels of ataxia telangiectasia and Rad3-related protein (ATR) were assessed by immunohistochemistry in clinical samples from patients with or without RT. Co-immunoprecipitation, mutagenesis, and Western blotting were used to measure the interactions between proteins. Xenograft experiments were performed to assess the tumor immune response in the mice. We identified a subset of PCa cells that exhibited resistance to RT, characterized by a reduced antigen presentation capability, which enhanced their ability to evade immune detection and resist cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. scRNA-seq revealed that the senescent state was a transient phase of PCa cells post-RT, particularly in CTLA-4 blockade treatment-resistant cells. This state was marked by increased cytosolic ATR level. Cytosolic ATR phosphorylated CD86 in its cytosolic domain and enhanced the interaction between CD86 and its E3 ligase MARCH1 through electrostatic attraction. Depletion or inhibition of Atr increased the sensitivity to immune attack and improved responses to anti-Ctla-4 antibody treatment in a mouse model. Our findings indicate that the activation of cytosolic ATR, which is associated with cellular senescence, impedes the effectiveness of combined RT and ICB treatments. This discovery may provide valuable insights for improving the efficacy of combined RT and ICB therapies in PCa.

Identification of a novel subtype of SPP1 + macrophages expressing SIRPα: implications for tumor immune evasion and treatment response prediction

BackgroundSPP1 + macrophages are among the major phagocytic cells, yet promoting tumor immune evasion and predicting unfavorable prognosis, in various cancer types. Meanwhile, the predictive value of the abundance of SPP1 + macrophages in patients receiving immunotherapy remains debatable, indicating the potential existence of subtypes of SPP1 + macrophages with diverse biological functions.MethodsThe single cell RNA sequencing data of myeloid cells integrated from several cancers including esophageal squamous cell carcinoma was analyzed for characterizing the function and cellular interactions of SPP1 + macrophages expressing SIRPα. Multiplexed immunohistochemistry was used to quantify the quantity and spatial distribution of SPP1 + macrophages expressing SIRPα. Kaplan–Meier method was used for survival analysis. In vitro and in vivo studies investigating the function of SPP1 + macrophages were performed.ResultsSPP1 + macrophages possessed a high phagocytic signature and could engulf more tumor cells in vitro and in vivo. SIRPα expression could represent the phagocytic activity of SPP1 + macrophages and delineated subsets of SPP1 + macrophages with different functions. SPP1 + SIRPα + macrophages showed close spatial distance to tumor cells and positively correlated with PD1 + CD8 + T cells. A high abundance of SPP1 + SIRPα + macrophages at baseline corresponded to patients’ response to PD-1/PD-L1 inhibitors.ConclusionA novel subtype of SPP1 + macrophages expressing SIRPα was identified and their abundance predicted patients’ response to PD-1/PD-L1 inhibitors.

Novel Spatial Approaches to Dissect the Lung Cancer Immune Microenvironment.

Lung cancer is a deadly disease with the highest rates of mortality. Over recent decades, a better understanding of the biological mechanisms implicated in its pathogenesis has led to the development of targeted therapies and immunotherapy, resulting in improvements in patient outcomes. To better understand lung cancer tumor biology and advance towards precision oncology, a comprehensive tumor profile is necessary. In recent years, novel in situ spatial multiomics approaches have emerged offering a more detailed view of the spatial location of tumor and tumor microenvironment cells, identifying their unique composition and functional status. In this sense, novel multiomics platforms have been developed to evaluate tumor heterogeneity, gene expression, metabolic reprogramming, signaling pathway activation, cell-cell interactions, and immune cell programs. In lung cancer research, several studies have used these spatial technologies to locate cells and associated them with histological features that are relevant to the pathogenesis of lung adenocarcinoma. These advancements may unveil further molecular and immune mechanisms in tumor biology that will lead to the discovery of biomarkers for treatment prediction and prognosis. In this review, we provide an overview of more widely used and emerging pathology-based approaches for spatial immune profiling in lung cancer and how they enhance our understanding of tumor biology and immune response.