Immunosuppressive Macrophages Research Articles

27 Spatial Clustering of Immunosuppressive Macrophages in Papillary Renal Cell Carcinoma

Abstract Background Papillary renal cell carcinoma (pRCC) accounts for up to 15% of all kidney cancer cases, yet our understanding of its tumor immune microenvironment (TIME) remains limited. We utilized multiplex immunofluorescence (mIF) and spatial transcriptomics (ST) to evaluate immune cell spatial architecture in pRCC and compared to that of clear cell RCC (ccRCC). Methods Surgical tumor specimens were obtained from localized RCC tumors, followed by mIF using markers for T cells, B cells, and tumor-associated macrophages (TAMs). Spatial data were derived in regions of interest (ROIs) manually selected from spatially distinct tissue compartments of the TIME. Single-cell ST was performed on a subset of patient samples, utilizing probes against 960 transcripts. Cell abundance, cell spatial clustering, and spatially varying gene expression were analyzed to identify unique features of the TIME in pRCC. Results Sixteen pRCC and 70 ccRCC patient samples underwent mIF. Compared to ccRCC, global pRCC immune cell abundance was statistically lower amongst functional CD8 T cells, while global cell spatial clustering was higher amongst M2-like macrophages as measured by mIF, including PDL1+ subsets. Using ST, seven genes were significantly associated with spatial clustering of M2-like macrophages in pRCC. Three of seven genes (CCL18, GPNMB, CD9) are known markers of lipid-associated TAMs (LAMs) (adjusted p-value < 0.1). Conclusions Compared to ccRCC, pRCC has fewer T cells but greater M2-like macrophage spatial clustering. Using ST, we found that multiple LAM-associated genes are spatially enriched in pRCC. Additional resources should be dedicated to investigating myeloid biomarkers and the impact of myeloid modulating therapeutics in pRCC.

Biomineralization-Tuned Nanounits Reprogram the Signal Transducer and Activator of Transcription 3 Signaling for Ferroptosis-Immunotherapy in Cancer Stem Cells.

Cancer stem cells (CSCs) are promising targets for improving anticancer treatment outcomes while eliminating recurrence, but their treatment remains a major challenge. Here, we report a nanointegrative strategy to realize CSC-targeted ferroptosis-immunotherapy through spatiotemporally controlled reprogramming of STAT3-regulated signaling circuits. Specifically, STAT3 inhibitor niclosamide (Ni) and an experimental ferroptosis drug (1S, 3R)-RSL3 (RSL3) are integrated into hyaluronic acid-modified amorphous calcium phosphate (ACP) nanounits through biomineralization (CaP-PEG-HA@Ni/RSL3), which could be recognized by CD44-overexpressing CSCs and released in a synchronized manner. Ni inhibits the CSC-intrinsic STAT3-PD-L1 axis to stimulate adaptive immunity and enhance interferon gamma (IFNγ) secretion by CD8+ T cells to downregulate SLC7A11 and SLC3A2 for blocking glutathione biosynthesis. Meanwhile, Ni-dependent STAT3 inhibition also upregulates ACSL4 through downstream signaling and IFNγ feedback. These effects cooperate with RSL3-mediated GPX4 deactivation to induce pronounced ferroptosis. Furthermore, CaP-PEG-HA@Ni/RSL3 also impairs the immunosuppressive M2-like tumor-associated macrophages, while Ca2+ ions released from degraded ACP could chelate with lipid peroxides in ferroptotic CSCs to avoid CD8+ T-cell inhibition, thus boosting the effector function of activated CD8+ T cells. This study offers a cooperative ferroptosis-immunotherapeutic approach for the treatment of refractory cancer.

Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors.

In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 create a TGF-β-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-induced apoptosis in part via activation of the NRF2 antioxidant program. Here, we examined how IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment. CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and released IL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expression of the lipid scramblase ATG9B, which exposed an "eat me" signal on the LO surface, leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1 receptor+ myeloid precursors into immunosuppressive macrophages. Blocking ATG9B's scramblase activity or depleting ANXA1 decreased niche macrophages and hindered tumor progression. Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternatively activated macrophage, with potential relevance to other settings of inflammation and tissue repair.

Remodeling the hepatic immune microenvironment and demolishing T cell traps to enhance immunotherapy efficacy in liver metastasis

Immune checkpoint inhibitors (ICIs) exhibit compromised therapeutic efficacy in many patients with advanced cancers, particularly those with liver metastases. Much of this incapability can be ascribed as an irresponsiveness resulting from the “cold” hepatic tumor microenvironment that acts as T cell “traps” for which there currently lack countermeasures. We report a novel nanomedicine that converts the hepatic immune microenvironment to a “hot” phenotype by targeting hepatic macrophage-centric T cell elimination. Using the nanomedicine, composed of KIRA6 (an endothelium reticulum stress inhibitor), α-Tocopherol nanoemulsions, and anti-PD1 antibodies, we found its potency in murine models of orthotopic colorectal tumors and hepatic metastases, restoring immune responses and enhancing anti-tumor effects. A post-treatment scrutiny of the immune microenvironment landscape in the liver reveals repolarization of immunosuppressive hepatic macrophages, upregulation of Th1-like effector CD4+ T cells, and rejuvenation of dendritic cells along with CD8+ T cells. These findings suggest adaptations of liver-centric immune milieu modulation strategies to improve the efficacy of ICIs for a variety of “cold” tumors and their liver metastases.

Biomarker analyses investigating disease biology and associations with outcomes in the JAVELIN Merkel 200 trial of avelumab in metastatic Merkel cell carcinoma.

Avelumab (anti-PD-L1) became the first approved treatment for metastatic Merkel cell carcinoma (mMCC) based on results from the phase 2 JAVELIN Merkel 200 trial. We report exploratory biomarker analyses from the trial. Patients with mMCC (n=88) with or without prior first-line chemotherapy received avelumab 10 mg/kg every 2 weeks. Analyses included: somatic mutations, mutational signatures, and tumor mutation burden from paired whole exome sequencing; gene, gene set, and immune content from RNAseq profiles; tumor PD-L1 and CD8 status from immunohistochemistry; and CD8 status from digital pathology. Tumors positive for Merkel cell polyomavirus (MCPyV) were characterized by an absence of driver mutations and a low tumor mutational burden, consistent with previous studies. A novel MCPyV-specific host gene expression signature was identified. MCPyV+ tumors had increased levels of immunosuppressive M2 macrophages in the tumor microenvironment, which appeared to correlate with PD-L1 expression; high CD8+ T-cell density in these tumors did not predict response to avelumab. Conversely, in patients with MCPyV- tumors, higher CD8+ T-cell density appeared to be associated with response. Mutations in several genes were associated with treatment outcomes. Compared with tumors sampled before chemotherapy, tumors sampled after chemotherapy had downregulated gene signatures for immune responses, including reduced expression of IFN-γ-related pathways. Levels of activated dendritic cells in responding patients were higher in patients assessed after vs before prior chemotherapy. Exploratory analyses provide insights into mMCC biology and potential associations with response to avelumab. Chemotherapy seems to negatively modulate the immune microenvironment.

Exploring the prognostic implications of cuproptosis-associated alterations in clear cell renal cell carcinoma via in vitro experiments

This study investigated the impact of novel copper ionophores on the prognosis of clear cell renal cell carcinoma (ccRCC) and the tumor microenvironment (TME). The differential expression of 10 cuproptosis and 40 TME-pathway-related genes were measured in 531 tumor samples and 71 adjacent kidney samples in The Cancer Genome Atlas database. A risk score model was constructed with LASSO cox to predict the prognosis of ccRCC patients. Forest plot and function enrichment were used to study the biological function of the key genes in depth. The study found that the risk score model accurately predicted the prognosis of ccRCC patients. Patients with high scores had higher immune responses with a higher proportion of anti-tumor lymphocytes and a lower proportion of immunosuppressive M2-like macrophages. However, the high-score group also exhibited a higher proportion of T follicular helper cells and regulatory T cells. These results suggest that cuproptosis-based therapy may be worth further investigation for the treatment of ccRCC and TME. Subsequently, by using RNAi, we established the stable depletion models of FDX1 and PDHB in ccRCC cell lines 786-O and ACHN. Through CCK8, colony formation, and Transwell assays, we observed that the knockdown of FDX1 and PDHB could significantly reduce the capabilities of proliferation and migration in ccRCC cells. In conclusion, this study illuminates the potential effectiveness of copper ionophores in the treatment of ccRCC, with higher risk scores correlating with better TME immune responses. It sets the stage for future cuproptosis-based therapy research in ccRCC and other cancers, focusing on copper’s role in TME.

Dietary restriction and fasting alleviate radiation-induced intestinal injury by inhibiting cGAS/STING activation

BackgroundRadiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy, limiting the clinical application of this treatment. Evidence shows the potential benefits of dietary restriction in improving metabolic profiles and age-related diseases. The present study investigated the effects and mechanisms of dietary restriction in radiation-induced intestinal injury. MethodsThe mice were randomly divided into the control group, 10 Gy total abdominal irradiation (TAI) group, and groups pretreated with 30% caloric restriction (CR) for 7 days or 24h fasting before TAI. After radiation, the mice were returned to ad libitum. The mice were sacrificed 3.5 days after radiation, and tissue samples were collected. ResultsCR and fasting reduced radiation-induced intestinal damage and promoted intestinal recovery by restoring the shortened colon length, improving the impaired intestinal structure and permeability, and remodeling gut microbial structure. CR and fasting also significantly reduced mitochondrial damage and DNA damage, which in turn reduced activation of the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) pathway and the production of type I interferon and other chemokines in the jejunum. Since the cGAS/STING pathway is linked with innate immunity, we further showed that CR and fasting induced polarization to immunosuppressive M2 macrophage, decreased CD8+ cytotoxic T lymphocytes, and downregulated proinflammatory factors in the jejunum. ConclusionsOur findings indicated that CR and fasting alleviate radiation-induced intestinal damage by reducing cGAS/STING-mediated harmful immune responses.

Novel insights into paclitaxel’s role on tumor-associated macrophages in enhancing PD-1 blockade in breast cancer treatment

BackgroundTriple-negative breast cancer (TNBC) poses unique challenges due to its complex nature and the need for more effective treatments. Recent studies showed encouraging outcomes from combining paclitaxel (PTX) with programmed...

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.

Monocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs' survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.

Transition Metal Oxide Nanomaterials: New Weapons to Boost Anti-Tumor Immunity Cycle.

Semiconductor nanomaterials have emerged as a significant factor in the advancement of tumor immunotherapy. This review discusses the potential of transition metal oxide (TMO) nanomaterials in the realm of anti-tumor immune modulation. These binary inorganic semiconductor compounds possess high electron mobility, extended ductility, and strong stability. Apart from being primary thermistor materials, they also serve as potent agents in enhancing the anti-tumor immunity cycle. The diverse metal oxidation states of TMOs result in a range of electronic properties, from metallicity to wide-bandgap insulating behavior. Notably, titanium oxide, manganese oxide, iron oxide, zinc oxide, and copper oxide have garnered interest due to their presence in tumor tissues and potential therapeutic implications. These nanoparticles (NPs) kickstart the tumor immunity cycle by inducing immunogenic cell death (ICD), prompting the release of ICD and tumor-associated antigens (TAAs) and working in conjunction with various therapies to trigger dendritic cell (DC) maturation, T cell response, and infiltration. Furthermore, they can alter the tumor microenvironment (TME) by reprogramming immunosuppressive tumor-associated macrophages into an inflammatory state, thereby impeding tumor growth. This review aims to bring attention to the research community regarding the diversity and significance of TMOs in the tumor immunity cycle, while also underscoring the potential and challenges associated with using TMOs in tumor immunotherapy.

Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance

AbstractMany individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy.

Diet and Tumor Genetics Conspire to Promote Prostate Cancer Metabolism and Shape the Tumor Microenvironment.

Obesity has been linked to prostate cancer in a stage-dependent manner, having no association with cancer initiation but correlating with disease progression in men with prostate cancer. Given the rising obesity rate and its association to aggressive prostate cancer, there is a growing need to understand the mechanisms underlying this relationship to identify patients at increased risk of lethal disease and inform therapeutic approaches. In this issue of Cancer Research, Boufaied and colleagues describe how diets high in saturated fatty acids promote MYC-driven prostate cancer. Leveraging MYC-expressing genetically engineered and allograft mouse models fed either a control low-fat or high-fat diet (HFD) enriched in saturated fatty acids, the authors found using digital pathology that HFD-fed mice exhibited increased tumor invasion. Metabolomics, transcriptomics, immunoblotting, and positron emission tomography of tumors from these mice demonstrated that a HFD promoted a metabolic shift in the tumors towards glycolysis. These preclinical data were supported by findings from two large clinical cohorts revealing that men diagnosed with prostate cancer and who consumed high levels of saturated fatty acids possessed tumors bearing glycolytic signatures. Deconvolution analyses and immunohistochemistry validation showed that these tumors also displayed increased angiogenesis and infiltration of immunosuppressive macrophages and regulatory T cells, the latter of which was also correlated with high saturated fat intake-associated glycolytic signatures in patient tumors. Together, these findings suggest that diets rich in saturated fatty acids, rather than obesity alone, accelerate MYC-driven prostate cancers through shifting tumor metabolism and shaping the tumor microenvironment. See related article by Boufaied et al., p. 1834.

Efficacy and biomarker analysis of phase 2 (P2) and window-of-opportunity (WoO) cohorts of patients with recurrent glioblastoma (rGBM) treated with ST101, an inhibitor of the transcription factor C/EBPβ.

2011 Background: CCAAT/enhancer-binding protein β (C/EBPβ) is an important transcription factor in GBM cell maintenance and is associated with worse outcomes and resistance to chemotherapy through transcription of genes associated with cell cycle and DNA repair. C/EBPβ is also required for maintenance of immunosuppressive tumor-associated macrophages. ST101 is a first-in-class antagonist of C/EBPβ that promotes selective GBM cell death without impacting normal cell viability (Darvishi, 2022), and repolarization of macrophages toward an immunostimulatory program. In an all comers P1 study, ST101 was well-tolerated, showed significant tumor uptake, ~40 hr plasma half-life, and signal of efficacy (1PR +8SD). With strong rationale targeting C/EBPβ in GBM and evidence that ST101 crosses the BBB in preclinical biodistribution studies, cohorts in rGBM were explored. Methods: Pts with ≤2 recurrences of GBM were enrolled in a P2 cohort (n=30) and treated with 500mg QW. A WoO cohort of 6 pts with rGBM received 2-4 doses of ST101 500mg QW prior to surgery and resumed ST101 after surgery until progression (NCT04478279). Endpoints for the two cohorts included response, PFS and OS while the WoO cohort also included tissue analyses (GBM subtypes, tumor microenvironment (TME) characterization, ST101 tumor penetration, and C/EBPβ target engagement). Clinical data is available for both cohorts and tissue analysis is available for the WoO cohort. Results: Data is a snapshot as of February 1, 2024. ST101 was safe and well-tolerated in both cohorts with no discontinuations due to AEs. Pts in the P2 study show 30% DCR (1PR + 8SD), 20% 6-mo PFS and 37% OS at 1 year. Median duration of treatment is 3.4 mos with 2 pts stable and still on study for 10+ and 16+ mos. In the WoO study, efficacy from post-surgery MRI showed 67% DCR (2 PR + 2 SD) and ~50% 6-mo PFS. Median OS cannot be assessed at this early stage. The median duration of treatment is 6.02 mos with 2 pts still on study for 7+ and 10+ mos. Tissue compared before and after ST101 exposure shows ST101 uptake and C/EBPβ target engagement by IHC, and pathologic evidence of treatment effect, such as geographic necrosis, in 5/6 pts. Evaluation of tumor and TME characteristics in post-ST101 treatment tissue will be presented. Conclusions: Monotherapy ST101 in pts with rGBM has an excellent safety profile and results in comparable outcomes to current 2nd line treatments. ST101 crosses the BBB, engages its target, and potentially induces treatment-related necrosis. These encouraging clinical activity, safety, and tissue findings, as well as preclinical data showing additive activity in combination with lomustine, support advancing ST101 to a randomized, placebo-controlled study comparing ST101 + lomustine vs. lomustine + placebo in rGBM. We aim to initiate this study in Q3 2024. Clinical trial information: NCT04478279 .

Breast cancer-associated fibroblasts maintain self-renewing immunosuppressive macrophages.

Breast cancer-associated fibroblasts maintain self-renewing immunosuppressive macrophages.

Spatial analysis of recurrent glioblastoma reveals perivascular niche organization.

Tumor evolution is driven by genetic variation; however, it is the tumor microenvironment (TME) that provides the selective pressure contributing to evolution in cancer. Despite high histopathological heterogeneity within glioblastoma (GBM), the most aggressive brain tumor, the interactions between the genetically distinct GBM cells and the surrounding TME are not fully understood. To address this, we analyzed matched primary and recurrent GBM archival tumor tissues with imaging-based techniques aimed to simultaneously evaluate tumor tissues for the presence of hypoxic, angiogenic, and inflammatory niches, extracellular matrix (ECM) organization, TERT promoter mutational status, and several oncogenic amplifications on the same slide and location. We found that the relationships between genetic and TME diversity are different in primary and matched recurrent tumors. Interestingly, the texture of the ECM, identified by label-free reflectance imaging, was predictive of single-cell genetic traits present in the tissue. Moreover, reflectance of ECM revealed structured organization of the perivascular niche in recurrent GBM, enriched in immunosuppressive macrophages. Single-cell spatial transcriptomics further confirmed the presence of the niche-specific macrophage populations and identified interactions between endothelial cells, perivascular fibroblasts, and immunosuppressive macrophages. Our results underscore the importance of GBM tissue organization in tumor evolution and highlight genetic and spatial dependencies.

Introducing Targeting Units or pH-Releasable Immunodrugs into Core-Clickable Nanogels

The development of nano-sized carrier systems plays a fundamental role in immunodrug delivery and the treatment of cancer. Especially functional materials, coupled with a stimuli-responsive drug release, control the selective delivery of small molecular drugs to the target site and avoid systemic side effects. Based on this, we introduce a DBCO core-functionalized nanogel platform for pH-reversible conjugation of highly potent TLR7/8-activating imidazoquinolines and the selective targeting of macrophage mannose receptor (MMR/ CD206) expressed by immunosuppressive macrophages. DBCO-PEG4-amine functionalized polymethacrylates are synthesized by controlled RAFT polymerization and self-assembled into precursor micelles in polar aprotic solvents. Corresponding nanogels are generated via reactive ester chemistry, while conjugated DBCO–units are incorporated into the core, still accessible for click reaction with azide-functionalized structures. Regarding the preparation of targeted nanogels, trimannose equipped with azide moieties can be conjugated to the DBCO nanogels, revealing the efficient targeting of macrophages’ mannose receptor in vitro. Moreover, the broad applicability of the DBCO nanogel is demonstrated by the synthesis of an azide–containing 2-propionic-3-methylmaleic anhydride-based linker sensitive for the pH–reversible conjugation of secondary amine-modified immune modulators, such as IMDQ-Me. Via bioorthogonal DBCO click reaction, the immune modulator can reversibly be conjugated, affording pH-responsive drug-loaded nanogels that conserve the desired immune stimulatory effect in vitro. Overall, these findings highlight the potential of core–functionalized DBCO nanogels, a promising carrier system for pH–sensitive conjugated immunodrugs as well as an attractive platform for controlled targeting of MMR. Altogether, the versatile application of core-functionalized DBCO nanogels may pave the way for enhancing bioorthogonal multifunctionality inside nanocarrier systems that assist in addressing multiple targets in cancer immunotherapy.

Abstract PR001: TRIM29 is required for basal bladder cancer invasive progression

Abstract TRIM29 (Tripartite Motif 29) also known ATDC, is an E3 ubiquitin ligase frequently upregulated in muscle-invasive bladder cancer (MIBC). We have previously shown TRIM29 global overexpression in a genetically engineered mouse model (GEMM) is sufficient to ` bladder cancer development and progression to MIBC. Other studies strongly suggest cytokeratin-5/14 (Krt5+/Krt14+) expressing basal-stem progenitor cells in the urothelium are the cells of origin for MIBC in mice. We therefore hypothesized that Trim29 expression in Krt5+ basal urothelial cells is required for development of MIBC in mice. To test this, we generated a GEMM harboring a Trim29 conditional KO allele and tamoxifen responsive Cre under control of the bovine Krt5promoter. Exposure of Krt5-CreERT2 Trim29flox/flox mice to tamoxifen resulted in activation of Cre and loss of Trim29 expression only in the Krt5+ basal urothelium. To induce bladder tumorigenesis, we utilized the urothelial specific carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in drinking water at 0.05%. After 6 months, tumor invasion was staged by a genitourinary pathologist based on depth of invasion: T1 (stromal invasive), T2 (muscle invasive) and T3 (deep muscle/peri-vesicular invasion). In agreement with previous studies, BBN exposure resulted in loss of Krt5-negative intermediate and superficial cells, and expansion of Krt5+/Krt14+ basal cells across the urothelium. In combination with a tamoxifen treatment this led to total Trim29 KO in the urothelium. All male Trim29 WT mice exposed to BBN developed Trim29+ bladder tumors, >50% of which demonstrated extensive progression to muscle-invasion (57% n=23). In contrast, only 16% of mice with Trim29 loss in Krt5+ basal cells developed MIBC (n=18). As an E3 ubiquitin ligase TRIM29 is known to target immune adaptor molecules, notably the stimulator of interferon genes (STING), for proteasomal degradation. We hypothesized TRIM29 targets STING during invasive progression and supports the establishment of an immune-privileged niche at the bladder cancer invasive front. We find TRIM29 expression in human bladder tissues is upregulated in the urothelium under stress and in MIBC tumors. In mice, BBN exposure upregulated Trim29 expression in the bladder urothelium which correlated with low urothelial Sting. In contrast, Krt5+ Trim29 loss resulted in significantly elevated Sting in the bladder urothelium. Multiplex immunofluorescence imaging and immunotyping of Trim29 KO mouse tissues revealed peritumoral enrichment of CD4+ and CD8+ T cells, CD206+ immunosuppressive macrophages, and CD4+FoxP3+ regulatory T cells. Taken together, these results suggest that TRIM29-mediated downregulation of STING in the bladder urothelium results in decreased immune surveillance at the tumor-stromal interface which expedites invasion and tumor burden. Citation Format: Alan Kelleher, Luke Broses, Yin Wang, Marian Henderson, Mark Day, Aaron Udager, Phillip Palmbos. TRIM29 is required for basal bladder cancer invasive progression [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr PR001.

Phosphoglycerate mutase 1 promotes breast cancer progression through inducing immunosuppressive M2 macrophages.

Immunosuppressive tumor microenvironment (TME) contributes to tumor progression and causes major obstacles for cancer therapy. Phosphoglycerate mutase 1 (PGAM1) is a key enzyme involved in cancer metabolism while its role in remodeling TME remains unclear. In this study, we reported that PGAM1 suppression in breast cancer (BC) cells led to a decrease in M2 polarization, migration, and interleukin-10 (IL-10) production of macrophages. PGAM1 regulation on CCL2 expression was essential to macrophage recruitment, which further mediated by activating JAK-STAT pathway. Additionally, the CCL2/CCR2 axis was observed to participate in PGAM1-mediated immunosuppression via regulating PD-1 expression in macrophages. Combined targeting of PGAM1 and the CCL2/CCR2 axis led to a reduction in tumor growth in vivo. Furthermore, clinical validation in BC tissues indicated a positive correlation between PGAM1, CCL2 and macrophage infiltration. Our study provides novel insights into the induction of immunosuppressive TME by PGAM1 and propose a new strategy for combination therapies targeting PGAM1 and macrophages in BC.

A bioactive nanocomposite integrated specific TAMs target and synergistic TAMs repolarization for effective cancer immunotherapy

Reactive oxygen species (ROS) generated from photosensitizers exhibit great potential for repolarizing immunosuppressive tumor-associated macrophages (TAMs) toward the anti-tumor M1 phenotype, representing a promising cancer immunotherapy strategy. Nevertheless, their effectiveness in eliminating solid tumors is generally limited by the instability and inadequate TAMs-specific targeting of photosensitizers. Here, a novel core-shell integrated nano platform is proposed to achieve a coordinated strategy of repolarizing TAMs for potentiating cancer immunotherapy. Colloidal mesoporous silica nanoparticles (CMSN) are fabricated to encapsulate photosensitizer-Indocyanine Green (ICG) to improve their stability. Then ginseng-derived exosome (GsE) was coated on the surface of ICG/CMSN for targeting TAMs, as well as repolarizing TAMs concurrently, named ICG/CMSN@GsE. As expected, with the synergism of ICG and GsE, ICG/CMSN@GsE exhibited better stability, mild generation of ROS, favorable specificity toward M2-like macrophages, enhancing drug retention in tumors and superior TAMs repolarization potency, then exerted a potent antitumor effect. In vivo, experiment results also confirm the synergistic suppression of tumor growth accompanied by the increased presence of anti-tumor M1-like macrophages and maximal tumor damage. Taken together, by integrating the superiorities of TAMs targeting specificity and synergistic TAMs repolarization effect into a single nanoplatform, ICG/CMSN@GsE can readily serve as a safe and high-performance nanoplatform for enhanced cancer immunotherapy.

A novel target to turn cold tumors into hot tumors: lysosomal 25-hydroxycholesterol activates AMPKα and immunosuppressive tumor-associated macrophages.

A novel target to turn cold tumors into hot tumors: lysosomal 25-hydroxycholesterol activates AMPKα and immunosuppressive tumor-associated macrophages.