Immune Suppressive Cells Research Articles

Abstract B028: Investigating immune activity caused by a novel anti-cancer cell penetrating peptide

Abstract Activating the immune system against cancerous cells represents a promising therapy against multiple cancer types, particularly breast cancer. The epidermal growth factor receptor (EGFR) represents an emerging target in immunotherapy. A novel anti-cancer cell penetrating peptide was recently discovered to affect immune recruitment and potentially function in a murine model of breast cancer. This peptide, termed cSNX1.3, is a targeted therapy to block the nuclear localization of the epidermal growth factor receptor (EGFR), a phenomenon thought to occur primarily in cancerous cells. This suggests that nuclear localized EGFR may play a role in suppressing an anti-cancer immune response. To gain a better understanding of this in vivo data, we used in vitro immune cell co-culture techniques, migration assays, and other techniques to investigate immune recruitment and function after cancer cells are treated with this novel peptide therapy. In addition, we are investigating the mechanism of cSNX1.3 mediated cell death to determine if it can induce immunogenic cell death. To determine if nuclear EGFR plays a role in immune cell suppression, we are using a CRISPR/Cas9 strategy to mutate the nuclear localization sequence. This will provide a valuable tool to better understand the seemingly cancer-specific trafficking phenomenon. Together, this work will expand our understanding of therapy induced immune cell recruitment and trafficking. Citation Format: Ryan Hecksel, Angelica Escoto, Joyce Schroeder. Investigating immune activity caused by a novel anti-cancer cell penetrating peptide [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B028.

The prognostic value and potential immunotherapeutic efficacy of ACVR1 in treating gastric cancer.

The discovery of biomarkers has facilitated the treatment of cancer. At present, the relationship between activin A receptor type-1 (ACVR1) and gastric cancer is gradually discovered. The aim of this study was to explore the expression of ACVR1 in gastric cancer and its clinical significance, to study the relationship between ACVR1 and tumor microenvironment (TME) for the prognosis of gastric cancer, and to further identify new targets for immunotherapy in gastric cancer. ACVR1 was first selected as a study gene according to several cancer and gastric cancer public datasets. Its pancancer expression was explored using the UCSC Xena database. The expression level, prognosis, and clinicopathological features of ACVR1 in gastric cancer were analyzed using The Cancer Genome Atlas (TCGA) database. Immunohistochemistry (IHC)-based experiments were conducted to study the expression of ACVR1 at the protein level. The IHC data were analyzed for correlations between ACVR1 expression and various clinicopathological factors and prognosis. The correlation of this gene with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, immune infiltration, immune checkpoints, drug therapy, tumor mutation burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) system was analyzed using R software. TCGA data showed that the expression of ACVR1 was higher in gastric cancer tissues than in paracancerous tissues. Moreover, the IHC experiments indicated that ACVR1 was upregulated in gastric cancer tissues at the protein level. Both univariate Cox and multivariate Cox results showed that the increase of ACVR1 was closely associated with tumor stage, size, lymph node metastasis, and age. High ACVR1 expression was linked to a poor prognosis of gastric cancer. The results also revealed that ACVR1 was closely related to suppressive immune cells and pathways. Analyses of immune checkpoints, antitumor drug, TMB, and immune microenvironment indicated that ACVR1 had an antitumor immune effect, promoting gastric cancer development and leading to poor immunotherapy. High ACVR1 expression can be used as an independent prognostic factor to predict the prognostic survival of patients with gastric cancer. ACVR1 expression in gastric cancer tissues was significantly correlated with immune infiltration and may thus serve as a potential therapeutic target for gastric cancer immunotherapy.

Upregulation of RACGAP1 is correlated with poor prognosis and immune infiltration in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a primary liver cancer with high mortality worldwide. Even though the patients with HCC received standard therapies, patients with HCC continue to experience unsatisfactory therapy outcomes. Presently, immune therapy acts as a novel therapeutic management for HCC. The aim of this study was to determine overexpressed genes in HCC and evaluate the association between overexpressed genes with the prognosis and immune infiltration. Gene expression profiles of HCC were analyzed using multiple online databases, and then confirmed by qualitative real time-polymerase chain reaction (RT-qPCR) and immunohistochemical analysis. The correlations of gene overexpression with the prognosis and immune infiltration were determined. Top 11 common differentially expressed genes were identified in HCC, and RACGAP1 was selected for further analysis. RACGAP1 expression was significantly higher in HCC tissues than that in normal tissues. Upregulation of RACGAP1 was correlated with clinical stage and poor prognosis. Additionally, RACGAP1 overexpression was positively related to the infiltration of suppressive immune cells. Moreover, we speculate RACGAP1 may promote tumorigenesis of HCC through immunosuppression mediated by YAP activation. Overexpression of RACGAP1 was associated with unfavorable prognosis and immune infiltration in HCC, which indicated that RACGAP1 could be a molecular target for HCC.

Unraveling the complex interplay between anti-tumor immune response and autoimmunity mediated by B cells and autoantibodies in the era of anti-checkpoint monoclonal antibody therapies.

The intricate relationship between anti-tumor immunity and autoimmunity is a complex yet crucial aspect of cancer biology. Tumor microenvironment often exhibits autoimmune features, a phenomenon that involves natural autoimmunity and the induction of humoral responses against self-antigens during tumorigenesis. This induction is facilitated by the orchestration of anti-tumor immunity, particularly within organized structures like tertiary lymphoid structures (TLS). Paradoxically, a significant number of cancer patients do not manifest autoimmune features during the course of their illness, with rare instances of paraneoplastic syndromes. This discrepancy can be attributed to various immune-mediated locks, including regulatory or suppressive immune cells, anergic autoreactive lymphocytes, or induction of effector cells exhaustion due to chronic stimulation. Overcoming these locks holds the risk to induce autoimmune mechanisms during cancer progression, a phenomenon notably observed with anti-immune checkpoint therapies, in contrast to more conventional treatments like chemotherapy or radiotherapy. Therefore, the challenge arises in managing immune-related adverse events (irAEs) induced by immune checkpoint inhibitors treatment, as decoupling them from the anti-tumor activity poses a significant clinical dilemma. This review summarizes recent advances in understanding the link between B-cell driven anti-tumor responses and autoimmune reactions in cancer patients, and discusses the clinical implications of this relationship.

Comprehensive molecular characteristics of clinical responses to PD-1 inhibitors plus anti-angiogenic agents (PA) in metastatic HER2-negative gastric adenocarcinoma.

279 Background: Anti-angiogensis agents were reported to enhance the efficacy of PD-1 inhibitor by inhibiting the infiltration of suppressive immune cell populations. Clinical studies indicated the synergistic anti-tumor effect of the combination of PD-1 inhibitors and anti-angiogenesis agents (PA). We aim to assess the efficacy of PA versus chemo-PA regiment in mGC, as well as the potential predictive biomarkers. Methods: A total of 55 GC tumors were analyzed using the next-generation sequencing (NGS), immunohistochemistry (IHC), and the tumor immune microenvironment (TIME) by multiplex immunofluorescence (mIHC). Clinical outcomes [Disease Control Rate (DCR), Progression-free survival (PFS) and overall survival (OS)] were compared between patients receiving PA treatment (n=32) and chemo-PA (n=23) treatment. Exploratory biomarker analyses were conducted for the prediction for the efficacy of PA/chemo-PA treatment. Results: Patients receiving PA regiment had comparable DCR (69% vs 50%, P =0.25) and PFS (median PFS: 6.53 vs 4.73 months, HR=0.70, 95%CI: 0.27-1.78, P =0.52), compared with those treated with combination of chemo-PA regiment as second or later-line treatment in mGC. Patients with HMCN1 wild-type showed significant improvements in DCR (77% vs 0%, P =0.023) and PFS (median PFS: 6.53 vs 1.17 months, P =0.0017), versus those with HMCN1 mutations in PA treatment cohort. HMCN1 mutations are associated with lower infiltration of endothelial cells and lower score of VEGF ligand-receptor interaction, according to the EPIC and pathway enrichment analysis ( P < 0.05). In addition, analysis of TIME by mIHC revealed that the fraction of CD68+ tumor-associated macrophages in the tumor center was higher in responders than non-responders before treatment (median: 17.59% vs 2.45%, P=0.016). Conclusions: PA regiment and chemo-PA regiment had similar efficacy in second or later line treatment of mGC. HMCN1 mutations maybe a predictive marker for PA regiment in HER2-negative mGC, which should be further validated in a large cohort.

The Role of Osteocytes in Pre-metastatic Niche Formation.

The formation of a pre-metastatic niche (PMN), in which primary cancer cells prime the distant site to be favorable to their engraftment and survival, may help explain the strong osteotropism observed in multiple cancers, such as breast and prostate. PMN formation, which includes extracellular matrix remodeling, increased angiogenesis and vascular permeability, enhanced bone marrow-derived cell recruitment and immune suppression, has mostly been described in soft tissues. In this review, we summarize current literature of PMN formation in bone. We also present evidence of a potential role for osteocytes to be the primary mediators of PMN development. Osteocytes regulate the bone microenvironment in myriad ways beyond canonical bone tissue remodeling, including changes that contribute to PMN formation. Perilacunar tissue remodeling, which has been observed in both bone and non-bone metastatic cancers, is a potential mechanism by which osteocyte-cancer cell signaling stimulates changes to the bone microenvironment. Osteocytes also protect against endothelial permeability, including that induced by cancer cells, in a loading-mediated process. Finally, osteocytes are potent regulators of cells within the bone marrow, including progenitors and immune cells, and might be involved in this aspect of PMN formation. Osteocytes should be examined for their role in PMN formation.

Acellular scaffold-based approach for in situ genetic engineering of host T-cells in solid tumor immunotherapy

BackgroundTargeted T-cell therapy has emerged as a promising strategy for the treatment of hematological malignancies. However, its application to solid tumors presents significant challenges due to the limited accessibility and heterogeneity. Localized delivery of tumor-specific T-cells using biomaterials has shown promise, however, procedures required for genetic modification and generation of a sufficient number of tumor-specific T-cells ex vivo remain major obstacles due to cost and time constraints.MethodsPolyethylene glycol (PEG)-based three-dimensional (3D) scaffolds were developed and conjugated with positively charged poly-L-lysine (PLL) using carbamide chemistry for efficient loading of lentiviruses (LVs) carrying tumor antigen-specific T-cell receptors (TCRs). The physical and biological properties of the scaffold were extensively characterized. Further, the scaffold loaded with OVA-TCR LVs was implanted in B16F10 cells expressing ovalbumin (B16-OVA) tumor model to evaluate the anti-tumor response and the presence of transduced T-cells.ResultsOur findings demonstrate that the scaffolds do not induce any systemic inflammation upon subcutaneous implantation and effectively recruit T-cells to the site. In B16-OVA melanoma tumor-bearing mice, the scaffolds efficiently transduce host T-cells with OVA-specific TCRs. These genetically modified T-cells exhibit homing capability towards the tumor and secondary lymphoid organs, resulting in a significant reduction of tumor size and systemic increase in anti-tumor cytokines. Immune cell profiling revealed a significantly high percentage of transduced T-cells and a notable reduction in suppressor immune cells within the tumors of mice implanted with these scaffolds.ConclusionOur scaffold-based T-cell therapy presents an innovative in situ localized approach for programming T-cells to target solid tumors. This approach offers a viable alternative to in vitro manipulation of T-cells, circumventing the need for large-scale in vitro generation and culture of tumor-specific T-cells. It offers an off-the-shelf alternative that facilitates the use of host cells instead of allogeneic cells, thereby, overcoming a major hurdle.

Anti-inflammatory effects of pulsed magnetic field on the immune system

When an inflammatory response occurs in the body, primary immune cells, such as macrophages, phagocytize and present antigens, and secondary immune cells, such as T cells, produce antibodies against the presented antigens to prevent infection in the body. Abnormalities in the immune system releases pro-inflammatory cytokines such as TNF-α and IL-6, leading to rheumatoid arthritis and sepsis. This study aimed to confirm the change in inflammatory activity across innate immunity and acquired immunity while investigating the effects of pulsed magnetic field (PMF) on the immune system to regulate excessive inflammation. Raw 264.7 and EL4 cells were co-cultured in a DMEM medium using permeable cell culture inserts and inflammation was induced using LPS. Our PMF stimulator has the maximum intensity of 4700 G at a transition time of 136 μs with pulse intervals of 1 Hz. In order to confirm anti-inflammatory effects of PMF, the level of IL-6, pH and mitochondrial respiration rate (MRR) were measured using ELISA, pH meter and MTT assay, respectively. It was observed in vitro that inflammation-induced macrophages induce activation of T cells, as evidenced by the faster acidification in pH, increased IL-6 expression, and enhanced MRR, compared to T cells. But after PMF stimulation, pH levels improved, the concentration of IL-6 reduced, and MRR decreased in both macrophages and T-cells, which indicates inflammation relief. Our results show that macrophages, the primary immune cells, are first involved in the inflammatory response and recovery and influence T cells, the secondary immune cells. Therefore PMF stimulus is thought to affect the immune system of the human body by balancing the activation and suppression of immune cells and improve anti-inflammation. For clinical use, non-invasive PMF can be developed as a medical devices modulating immune system with optimizing the PMF conditions such as pulse shape, duration, or repetition rate.

The immune landscape of sepsis and using immune clusters for identifying sepsis endotypes.

The dysregulated immune response to sepsis still remains unclear. Stratification of sepsis patients into endotypes based on immune indicators is important for the future development of personalized therapies. We aimed to evaluate the immune landscape of sepsis and the use of immune clusters for identifying sepsis endotypes. The indicators involved in innate, cellular, and humoral immune cells, inhibitory immune cells, and cytokines were simultaneously assessed in 90 sepsis patients and 40 healthy controls. Unsupervised k-means cluster analysis of immune indicator data were used to identify patient clusters, and a random forest approach was used to build a prediction model for classifying sepsis endotypes. We depicted that the impairment of innate and adaptive immunity accompanying increased inflammation was the most prominent feature in patients with sepsis. However, using immune indicators for distinguishing sepsis from bacteremia was difficult, most likely due to the considerable heterogeneity in sepsis patients. Cluster analysis of sepsis patients identified three immune clusters with different survival rates. Cluster 1 (36.7%) could be distinguished from the other clusters as being an "effector-type" cluster, whereas cluster 2 (34.4%) was a "potential-type" cluster, and cluster 3 (28.9%) was a "dysregulation-type" cluster, which showed the lowest survival rate. In addition, we established a prediction model based on immune indicator data, which accurately classified sepsis patients into three immune endotypes. We depicted the immune landscape of patients with sepsis and identified three distinct immune endotypes with different survival rates. Cluster membership could be predicted with a model based on immune data.

Chemotherapy Resistance in Cancer: Mechanism and Roadmap to Evade Exploring Apoptosis

Chemotherapy resistance indicates the non-responsiveness of cancer cells to the cytotoxic and inhibitory effects of chemo drugs attributed to either intrinsic or extrinsic resistance mechanisms in cancer cells. Studies so far indicate that drug resistance can be triggered by a multitude of factors such as the over-expression of drug efflux pumps, DNA repair mechanisms, modifications in the drug target such as point mutations and gene amplification, over-expression of anti-apoptotic proteins and down-regulation of pro-apoptotic signals, presence of cancer stem cells and immune-suppressive cells, excessive cytokine production, tumor heterogeneity, epigenetic changes, activation of alternate pro-survival signaling pathways, etc. Both host and tumor-related factors can contribute to therapy resistance. Currently, chemo resistance poses the foremost setback in the successful treatment of cancer, and it exerts significant stress on the available medical resources. Besides the costs associated with the treatment, patients go through severe emotional and physical trauma. Chemotherapy resistance is also a major contributor to accelerated metastasis and invasion. Dose-escalation is not always practical since the associated side effects may increase apart from increasing the treatment costs. Several studies are ongoing to address this issue productively, such as therapeutic molecules designed to restore the apoptotic machinery. Site-specific delivery of pro-apoptotic agents such as small molecules, antibodies, peptides, etc. targeting the apoptosis pathway is also thoroughly studied. Moreover, the efficacy of combination strategies is also a topic of research.

In vitro generation of murine myeloid-derived suppressor cells from hematopoietic progenitor cells.

One of the hallmarks of cancer is the expansion and accumulation of highly immunosuppressive myeloid cells known as myeloid-derived suppressor cells (MDSCs). To study MDSCs biology, differentiation from hematopoietic progenitor cells (HPC) is an useful tool to elucidate the biological and biochemical mechanisms associated with acquisition of immune suppressive activity and expansion in cancer. Although this is one of the protocols performed to study immune suppressive myeloid cells, differentiation of MDSCs from HPC is a method that allows to modify conditions of the supernatants used. In this protocol, we outline the process of differentiating HPCs into MDSCs in vitro using tumor explant supernatants to recapitulate the tumor microenvironment.

Immune Evasion in Cancer Is Regulated by Tumor-Asociated Macrophages (TAMs): Targeting TAMs.

Recent advancements in cancer treatment have explored a variety of approaches to address the needs of patients. Recently, immunotherapy has evolved as an efficacious treatment for various cancers resistant to conventional therapies. Hence, significant milestones in immunotherapy were achieved clinically in a large subset of cancer patients. Unfortunately, some cancer types do not respond to treatment, and among the responsive cancers, some patients remain unresponsive to treatment. Consequently, there is a critical need to examine the mechanisms of immune resistance and devise strategies to target immune suppressor cells or factors, thereby allowing for tumor sensitivity to immune cytotoxic cells. M2 macrophages, also known as tumor-associated macrophages (TAMs), are of interest due to their role in suppressing the immune system and influencing antitumor immune responses through modulating T cell activity and immune checkpoint expression. TAMs are associated with signaling pathways that modulate the tumor microenvironment (TME), contributing to immune evasion. One approach targets TAMs, focusing on preventing the polarization of M1 macrophages into the protumoral M2 phenotype. Other strategies focus on direct or indirect targeting of M2 macrophages through understanding the interaction of TAMs with immune factors or signaling pathways. Clinically, biomarkers associated with TAMs' immune resistance in cancer patients have been identified, opening avenues for intervention using pharmacological agents or immunotherapeutic approaches. Ultimately, these multifaceted approaches are promising in overcoming immune resistance and improving cancer treatment outcomes.

IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis.

Rationale: Nab-paclitaxel (Abx) is widely employed in malignant tumor therapy. In tumor cells and pro-tumoral M2-type macrophages, the IL4 receptor (IL4R) is upregulated. This study aimed to elucidate the selective delivery of Abx to M2-type macrophages by targeting IL4R and reprogramming them into an anti-tumoral M1-type. Methods: Abx was conjugated with the IL4R-binding IL4RPep-1 peptide using click chemistry (IL4R-Abx). Cellular internalization, macrophage reprogramming and signal pathways, and tumor growth and metastasis by IL4R-Abx were examined. Results: IL4R-Abx was internalized into M2 macrophages more efficiently compared to the unmodified Abx and control peptide-conjugated Abx (Ctrl-Abx), which was primarily inhibited using an anti-IL4R antibody and a receptor-mediated endocytosis inhibitor compared with a macropinocytosis inhibitor. IL4R-Abx reprogrammed the M2-type macrophages into M1-like phenotype and increased reactive oxygen species (ROS) levels and extracellular release of high mobility group box 1 (HMGB1) in M2 macrophages at higher levels than Abx and Ctrl-Abx. The conditioned medium of IL4R-Abx-treated M2 macrophages skewed M2 macrophages into the M1-like phenotype, in which an anti-HMGB1 antibody and a toll-like receptor 4 (TLR4) inhibitor induced a blockade. IL4R-Abx accumulated at tumors, heightened immune-stimulatory cells while reducing immune-suppressing cells, and hampered tumor growth and metastasis in mice more efficiently than Abx and Ctrl-Abx. Conclusions: These results indicate that IL4R-targeting allows enhancement of M2-macrophage shaping into M1-like phenotype by Abx through the ROS-HMGB1-TLR4 axis, improvement of antitumor immunity, and thereby inhibition of tumor growth and metastasis, presenting a new approach to cancer immunotherapy.

Harnessing Immunity to Treat Advanced Thyroid Cancer.

The incidence of thyroid cancer (TC) has increased over the past 30 years. Although differentiated thyroid cancer (DTC) has a good prognosis in most patients undergoing total thyroidectomy followed by radioiodine therapy (RAI), 5-10% of patients develop metastasis. Anaplastic thyroid cancer (ATC) has a low survival rate and few effective treatments have been available to date. Recently, tyrosine kinase inhibitors (TKIs) have been successfully applied to RAI-resistant or non-responsive TC to suppress the disease. However, TC eventually develops resistance to TKIs. Immunotherapy is a promising treatment for TC, the majority of which is considered an immune-hot malignancy. Immune suppression by TC cells and immune-suppressing cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, is complex and dynamic. Negative immune checkpoints, cytokines, vascular endothelial growth factors (VEGF), and indoleamine 2,3-dioxygenase 1 (IDO1) suppress antitumor T cells. Basic and translational advances in immune checkpoint inhibitors (ICIs), molecule-targeted therapy, tumor-specific immunotherapy, and their combinations have enabled us to overcome immune suppression and activate antitumor immune cells. This review summarizes current findings regarding the immune microenvironment, immunosuppression, immunological targets, and immunotherapy for TC and highlights the potential efficacy of immunotherapy.

Role of Exosomes in Epithelial-Mesenchymal Transition.

Epithelial-mesenchymal transition (EMT) is a fundamental process driving cancer metastasis, transforming non-motile cells into a motile population that migrates to distant organs and forms secondary tumors. In recent years, cancer research has revealed a strong connection between exosomes and the EMT. Exosomes, a subpopulation of extracellular vesicles, facilitate cellular communication and dynamically regulate various aspects of cancer metastasis, including immune cell suppression, extracellular matrix remodeling, metastasis initiation, EMT initiation, and organ-specific metastasis. Tumor-derived exosomes (TEXs) and their molecular cargo, comprising proteins, lipids, nucleic acids, and carbohydrates, are essential components that promote EMT in cancer. TEXs miRNAs play a crucial role in reprogramming the tumor microenvironment, while TEX surface integrins contribute to organ-specific metastasis. Exosome-based cancer metastasis research offers a deeper understanding about cancer and an effective theranostic platform development. Additionally, various therapeutic sources of exosomes are paving the way for innovative cancer treatment development. In this Review, we spotlight the role of exosomes in EMT and their theranostic impact, aiming to inspire cancer researchers worldwide to explore this fascinating field in more innovative ways.

Tumor Microenvironment Modulating CaCO3 -Based Colloidosomal Microreactors Can Generally Reinforce Cancer Immunotherapy.

Tumor hypoxia and acidity, two general features of solid tumors, are known to have negative effect on cancer immunotherapy by directly causing dysfunction of effector immune cells and promoting suppressive immune cells inside tumors. Herein, a multifunctional colloidosomal microreactor is constructed by encapsulating catalase within calcium carbonate (CaCO3 ) nanoparticle-assembled colloidosomes (abbreviated as CaP CSs) via the classic double emulsion method. The yielded CCaP CSs exhibit well-retained proton-scavenging and hydrogen peroxide decomposition performances and can thus neutralize tumor acidity, attenuate tumor hypoxia, and suppress lactate production upon intratumoral administration. Consequently, CCaP CSs treatment can activate potent antitumor immunity and thus significantly enhance the therapeutic potency of coloaded anti-programmed death-1 (anti-PD-1) antibodies in both murine subcutaneous CT26 and orthotopic 4T1 tumor xenografts. In addition, such CCaP CSs treatment also markedly reinforces the therapeutic potency of epidermal growth factor receptor expressing chimeric antigen receptor T (EGFR-CAR-T) cells toward a human triple-negative breast cancer xenograft by promoting their tumor infiltration and effector cytokine secretion. Therefore, this study highlights that chemical modulation of tumor acidity and hypoxia can collectively reverse tumor immunosuppression and thus significantly potentiate both immune checkpoint blockade and CAR-T cell immunotherapies toward solid tumors.

IPSC-derived natural killer cells expressing the FcγR fusion CD64/16A can be armed with antibodies for multitumor antigen targeting

BackgroundAntibody therapies can direct natural killer (NK) cells to tumor cells, tumor-associated cells, and suppressive immune cells to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). This antigen-specific effector function of human NK...

Abstract LB_C15: PI3Kδ/γ inhibitor as a novel immune-regulatory radiosensitizer

Abstract Radiotherapy is known to augment anti-tumor immunity, yet its concurrent induction of immunosuppressive responses presents a significant obstacle to efficacious treatment. This study showed that a new PI3Kδ/γ inhibitor along with irradiation promotes systemic anti-tumor immunity and abscopal response by reducing activity of immune suppressive cells. The combination systemically decreased proliferation of regulatory T cells (Tregs) and enhanced the number of tumor specific CD8a+ T cells in tumor microenvironment, thereby leading to tumor regression. Interestingly, this effect lasts for 14 days after radiation and even causes distant tumors to regress, known as the abscopal effect. Moreover, molecular analysis shows that the combination treatment creates immune-stimulatory tumor microenvironment in tumors, suggesting that the combined therapy converts immune cold tumor into hot. These findings highlight the promise of using PI3Kδ/γ inhibitors to enhance anti-tumor immunity in solid tumors treated with radiotherapy, providing the evidence for the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer. Citation Format: Yi Na Yoon, Jae-Sung Kim. PI3Kδ/γ inhibitor as a novel immune-regulatory radiosensitizer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C15.

Abstract B009: GBM cells mimic regulatory T cell function to protect the CSC pool from immune surveillance in recurrent GBM

Abstract Glioblastoma (GBM) is the most lethal and aggressive form of brain cancer, with incredibly high recurrence rates and virtually no long-term survival. Despite our growing understanding of GBM at the molecular level, we still don’t fully comprehend the molecular mechanisms driving recurrence in GBM. Current knowledge indicates that Glioma Stem Cells (GSCs) drive a resistant cell phenotype in GBM. Understanding the molecular events coordinated by GSCs leading to therapy-resistance can provide key advancements on how we treat recurrent GBM (rGBM). Mechanisms of GSC immune escape are considered fundamental to clinical GBM growth and recurrence. The cross talk between cancer cells and the immune system is now classified as a hallmark of cancer. The current dogma is that cancer cells, including GSCs, influence recruitment of immune-suppressive cell subsets to tumor tissue, however how subsets of GSCs mimic this immune-suppressive effect within the tumor microenvironment remains to be elucidated. Single-cell RNA sequencing analysis of GBM neurospheres revealed a previously unrecognized Oct4/Sox2high/FOXP3− cell subpopulation with high expression of TGFb1, CD39, CD73, PD-L1, and Galectin-1, a gene expression fingerprint typically associated with regulatory T cell (Tregs) and their immune suppressive functions within the tumor microenvironment. Bioinformatics analysis of public databases shows that the above-mentioned genes are enriched in the mesenchymal GBM subtype and highly correlated with TGFb type II receptor (TGFBR2) expression in clinical GBM. Mechanistically, we show that blocking TGFBR2 or XBP1 signaling, key intermediary of this process, counteracts the immune-suppressive phenotype of rGBM cells by restoring CD4 and CD8 tumor killing capacity and reversing exhaustion. By combining miRNA-based network analysis and advanced nanoparticle formulation for miRNA delivery we show that miR-16/124-3p effectively target all nodes of this immunosuppressive axis successfully blocking the immunosuppressive nature of rGBM cells. This research provides the first description of such neoplastic cells in any malignancy and has high potential translational impact since targeting these tumor cell subsets and their immunosuppressive mechanisms may be critical to the successful development of GBM immunotherapies. Citation Format: Hernando Lopez-Bertoni, Sophie Sall, Harmon Khela, Jack Korleski, Katherine Luly, Maya Johnson, Amanda Johnson, Jordan Green, John Laterra. GBM cells mimic regulatory T cell function to protect the CSC pool from immune surveillance in recurrent GBM [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 B009.

Clinical and Immunologic Features of Germline Pathogenic Variant-Positive Patients with Melanoma.

Malignant melanoma represents the most lethal skin cancer with germline predispositions thought to comprise 10% to 15% of all melanoma cases. No studies to date examine the immunologic features that may differentiate survival differences between germline pathogenic variant (gPV)-positive patients with melanoma from gPV-negative patients with melanoma. Adult patients with melanoma and clinical characteristics suggesting hereditary predisposition to cancer were prospectively recruited to undergo germline testing and flow cytometric analysis of peripheral immune suppressor cells. In this cohort, gPV-positive patients (n = 72) had a significantly improved melanoma-specific survival (MSS) compared with gPV-negative patients (n = 411; HRadj, 0.32; 95% CI, 0.13-0.82; P = 0.01). These survival improvements among gPV-positive patients were most apparent among cutaneous melanoma subtypes (HRadj, 0.12; 95% CI, 0.016-0.86; P = 0.03) and numerically improved in later-stage (IIB-IV) patients (HRadj, 0.34; 95% CI, 0.10-1.11; P = 0.06). Further, gPV-positive patients had a significantly lower level of total circulating PMN-MDSC compared with gPV-negative patients (P = 0.01), which was most apparent in those diagnosed with later stages (IIB-IV) of melanoma (P = 0.009). Finally, a significant upregulation of inflammatory transcriptome signatures in later-stage gPV-positive patients (n = 21) was observed in comparison with gPV-negative patients (n = 173) in the cutaneous melanoma cohort (SKCM) of The Cancer Genome Atlas (TCGA). gPV-positive patients with melanoma exhibit improved MSS in addition to reduced peripheral PMN-MDSC and an enhanced inflammatory microenvironment.