PD-1 Immune Checkpoint Research Articles

Intracranial administration of anti-PD-1 and anti-CTLA-4 immune checkpoint-blocking monoclonal antibodies in patients with recurrent high-grade glioma.

Recurrent high-grade glioma (rHGG) lacks effective life-prolonging treatments and the efficacy of systemic PD-1 and CTLA-4 immune checkpoint inhibitors is limited. The multi-cohort Glitipni phase I trial investigates the safety and feasibility of intraoperative intracerebral (iCer) and postoperative intracavitary (iCav) nivolumab (NIVO) ± ipilimumab (IPI) treatment following maximal safe resection (MSR) in rHGG. Patients received 10mg IV NIVO within 24h before surgery, followed by MSR, iCer 5mg IPI and 10mg NIVO, and Ommaya catheter placement in the resection cavity. Biweekly postoperative iCav administrations of 1-5-10mg NIVO (cohort 4) or 10mg NIVO plus 1-5-10mg IPI (cohort 7) were combined with 10mg IV NIVO for 11 cycles. 42 rHGG patients underwent MSR with iCer NIVO + IPI. 16 pts were treated in cohort 4 (postoperative iCav NIVO at escalating doses) while 28 patients were treated in cohort 7 (intra and postoperative iCav NIVO and escalating doses of IPI). The most common TRAE was fatigue; no grade 5 AE occurred. Dose-limiting toxicity was grade 3 neutrophilic pleocytosis (4 pts) receiving iCav NIVO plus 5 or 10mg IPI. PFS and OS did not significantly differ between cohorts (median OS: 42 [95% CI 26-57] vs. 35 [29-40] weeks; 1-year OS rate: 37% vs. 29%). Baseline B7-H3 expression significantly correlated with worse survival. OS compared favorably to a historical pooled cohort (n = 469) of Belgian rHGG pts treated with anti-VEGF therapies (log-rank P = .015). Intraoperative iCer IPI + NIVO with postoperative iCav NIVO±IPI up to biweekly doses of 1mg IPI + 10mg NIVO is feasible and safe, showing encouraging OS in rHGG patients. ClinicalTrials.gov registration: NCT03233152.

Human papillomavirus-encoded circular RNA circE7 promotes immune evasion in head and neck squamous cell carcinoma

Immune evasion represents a crucial milestone in the progression of cancer and serves as the theoretical foundation for tumor immunotherapy. In this study, we reveal a negative association between Human Papillomavirus (HPV)-encoded circular RNA, circE7, and the infiltration of CD8+ T cells in head and neck squamous cell carcinoma (HNSCC). Both in vitro and in vivo experiments demonstrate that circE7 suppresses the function and activity of T cells by downregulating the transcription of LGALS9, which encodes the galectin-9 protein. The molecular mechanism involves circE7 binding to acetyl-CoA carboxylase 1 (ACC1), promoting its dephosphorylation and thereby activating ACC1. Activated ACC1 reduces H3K27 acetylation at the LGALS9 gene promoter, leading to decreased galectin-9 expression. Notably, galectin-9 interacts with immune checkpoint molecules TIM-3 and PD-1, inhibiting the secretion of cytotoxic cytokines by T cells and promoting T cell apoptosis. Here, we demonstrate a mechanism by which HPV promotes immune evasion in HNSCC through a circE7-driven epigenetic modification and propose a potential immunotherapy strategy for HNSCC that involves the combined use of anti-PD-1 and anti-TIM-3 inhibitors.

Evaluation of the efficacy of combined immune checkpoint inhibitors in advanced melanoma treatment - Long term outcomes and emerging therapeutic perspectives: a narrative review

Combination therapy with immune checkpoint inhibitors, specifically CTLA-4 and PD-1 blockade, has shown promise in treating advanced melanoma. However, this approach often results in increased toxicity, necessitating a careful evaluation of both efficacy and safety. This review explores clinical outcomes, survival rates, and adverse events associated with these therapies. A systematic review of PubMed, Scopus, and clinical trial databases was conducted for studies published from 2014 to 2024. Studies assessing the combined use of CTLA-4 and PD-1 inhibitors in melanoma patients were included, focusing on overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). The combination of CTLA-4 and PD-1 inhibitors significantly improved clinical outcomes in advanced melanoma. In trials like CheckMate 067, the five-year overall survival rate reached 52%, with a notable improvement in progression-free survival. However, these benefits came with substantial toxicity, as approximately 55% of patients experienced grade 3 or 4 treatment-related adverse events, including colitis, hepatitis, and pneumonitis. Despite these challenges, combination therapy led to durable responses in a subset of patients, underscoring its efficacy. The review emphasizes the need for balancing efficacy with toxicity management in clinical practice. While CTLA-4 and PD-1 inhibitor combinations improve survival in advanced melanoma, increased toxicity presents challenges. Further research is needed to optimize treatment strategies and enhance patient selection to balance efficacy and safety.

Comparative Analysis of Inhibitory and Activating Immune Checkpoints PD-1, PD-L1, CD28, and CD86 in Non-Melanoma Skin Cancer.

The establishment of immunotherapy applying immune checkpoint inhibitors (ICI) has provided an important new option for the treatment of solid malignant diseases. However, different tumor entities show dramatically different responses to this therapy. BCC responds worse to anti-PD-1 ICIs as compared to cSCC. Differential immune checkpoint expression could explain this discrepancy and, therefore, the aim of this study was to analyze activating and inhibitory immune checkpoints in cSCC and BCC tissues. Tissue microarrays of the invasive front as well as the tumor core of BCC and cSCC samples were used to evaluate PD-1, PD-L1, CD28, and CD86 expression and their topographic distribution profiles by chromogenic immunohistochemistry. QuPath was used to determine the labeling index. The expression of PD-1, PD-L1, and CD28 was significantly higher in both the tumor core and the invasive front of cSCC samples as compared to BCC (p < 0.001). In addition, the ratios of PD-L1/CD86 (p < 0.001) and CD28/CD86 (p < 0.001) were significantly higher in cSCC. The invasive front of both tumor entities showed higher expression levels of all immune markers compared to the tumor core in both tumor entities. The significantly higher expression of PD-1, PD-L1, and CD28 in cSCC, along with the predominance of the inhibitory ligand PD-L1 as compared to the activating CD86 in cSCC, provide a potential explanation for the better objective response rates to anti-PD-1 immunotherapy as compared to BCC. Furthermore, the predominant site of interaction between the immune system and the tumor was within the invasive front in both tumor types.

Targeted inhibition of glycogen synthase kinase-3 using 9-ING-41 (elraglusib) enhances CD8 T-cell-reactivity against neuroblastoma cells

The prognosis of patients with high-risk neuroblastoma remains poor, partly due to inadequate immune recognition of the tumor. Neuroblastomas display extremely low surface MHC-I, preventing recognition by cytotoxic T lymphocytes (CTLs) and contributing to an immunosuppressive tumor microenvironment. Glycogen synthase kinase-3 beta (GSK-3β) is involved in pathways that may affect the MHC-I antigen processing and presentation pathway. We proposed that therapeutic inhibition of GSK-3β might improve the surface display of MHC-I molecules on neuroblastoma cells, and therefore tested if targeting of GSK-3β using the inhibitor 9-ING-41 (Elraglusib) improves MHC-I-mediated CTL recognition. We analyzed mRNA expression data of neuroblastoma tumor datasets and found that non-MYCN-amplified neuroblastomas express higher GSK-3β levels than MYCN-amplified tumors. In non-MYCN-amplified cells SH-SY5Y, SK-N-AS and SK-N-SH 9-ING-41 treatment enhanced MHC-I surface display and the expression levels of a subset of genes involved in MHC-I antigen processing and presentation. Further, 9-ING-41 treatment triggered increased STAT1 pathway activation, upstream of antigen presentation pathways in two of the three non-MYCN-amplified cell lines. Finally, in co-culture experiments with CD8 + T cells, 9-ING-41 improved immune recognition of the neuroblastoma cells, as evidenced by augmented T-cell activation marker levels and T-cell proliferation, which was further enhanced by PD-1 immune checkpoint inhibition. Our preclinical study provides experimental support to further explore the GSK-3β inhibitor 9-ING-41 as an immunomodulatory agent to increase tumor immune recognition in neuroblastoma.

Abstract B058: Rewiring CD8+ T cell responses to PD-1 immune checkpoint blockade in PDAC via the inhibitory receptor PSGL-1

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, poorly immunogenic cancer and non-responsive to all currently available treatments, including immune checkpoint blockade (ICB) therapies. As survival rates remain low (13%), there is an urgent need for new therapeutic options. A hallmark of PDAC is the limited infiltration of anti-tumor cytotoxic CD8+ T cells. Analysis of single-cell RNA-sequencing data of PDAC tumors from treatment naïve patients reveals high expression of P-selectin glycoprotein ligand 1 (PSGL-1) on tumor-infiltrating CD8+ T cells. PSGL-1 is an intrinsic negative regulator of CD8+ T cells that promotes the development of functional exhaustion. We therefore hypothesized that PSGL-1-mediated immune suppression is a critical barrier to effective anti-tumor immunity in PDAC. To test this, we used preclinical models of orthotopic injection PDAC tumor cells into pancreata, recapitulating patient responses to PDAC with limited T cell infiltrates and uncontrolled tumor growth in C57BL/6 (wildtype) control mice and compared anti-tumor immune responses in PSGL-1KO (C57BL/6 background) mice. At 28 days post-injection of KPC.4662 PDAC tumor cells, tumor burden in PSGL-1KO mice was reduced by &amp;gt;50% compared to controls, with 45% of PSGL-1KO animals exhibiting &amp;gt;70% reduction. Total immune infiltration (CD45+) was 2-fold greater in tumors from PSGL-1KO mice, with significant increases in infiltrating CD4+ and CD8+ T cells. Detailed analyses revealed that infiltrating CD8+ T cells from PSGL-1KO mice were less terminally differentiated towards exhaustion. PSGL-1KO PD-1+ CD8+ T cells expressed less TOX expression and fewer cells co-expressed CD38 and CD101 while more expressed CX3CR1 compared to controls. Intratumoral PSGL-1KO CD8+ T cells also retained greater functionality as well as indicated by inflammatory cytokine production (IFNg, TNFa) and Granzyme B expression. Moreover, PSGL-1KO mice showed protection against metastatic disease to the lungs. We find that protection by PSGL-1KO mice is T cell dependent as transient depletion of CD4+ and CD8+ T cells prior to tumor cell implantation results in the loss of PDAC tumor growth inhibition by PSGL-1KO mice. Less-differentiated, proliferation-competent precursors of exhausted CD8+ T cells (TPEX) are essential to PD-1 ICB responsiveness in patients and preclinical models. Given that PSGL-1-deficiency limits terminal differentiation of CD8+ T cells in PDAC, we hypothesized that PSGL-1-deficiency would promote responsiveness to PD-1 ICB, which is ineffective as a monotherapy in PDAC patients and mouse models. While therapeutic treatment with anti-PD-1 had no effect on the tumor growth in the control animals, PD-1 ICB resulted in tumor ablation in 85% of PSGL-1KO animals, demonstrating a profound synergistic effect of PD-1 inhibition in the absence of PSGL-1. From these studies, we conclude that PSGL- 1 is a critical inhibitor anti-tumor T cell immunity in PDAC and represents a novel ICB target with high translational potential for promoting immune responses to PDAC tumors. Citation Format: Jennifer L Hope, Yijuan Zhang, Hannah A. F. Hetrick, Evelyn S. Sanchez Hernandez, Gabriele Romano, Sreeja Roy, Michelle Lin, Ashley B Palete, Swetha Maganti, Dennis C Otero, Katelyn T Byrne, Cosimo Commisso, Linda M Bradley. Rewiring CD8T cell responses to PD-1 immune checkpoint blockade in PDAC via the inhibitory receptor PSGL-1 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B058.

Targeting GProtein-Coupled Receptors in Immuno-Oncological Therapies.

The advent of cancer immunotherapy based on PD-1 and CTLA-4 immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, many cancers do not respond to ICB, highlighting the urgent need for additional approaches to achieve durable cancer remission. The large family of G protein-coupled receptors (GPCRs) is the target of more than 30% of all approved drugs, but GPCRs have been underexploited in cancer immunotherapy. In this review, we discuss the central role of GPCRs in immune cell migration and function and describe how single-cell transcriptomic studies are illuminating the complexity of the human tumor immune GPCRome. These receptors include multiple GPCRs expressed in CD8 Tcells that are activated by inflammatory mediators, protons, neurotransmitters, and metabolites that accumulate in the tumor microenvironment, thereby promoting Tcell dysfunction. We also discuss new opportunities to target GPCRs as a multimodal approach to enhance the response to ICB for a myriad of human malignancies.

Revolutionizing Skin Cancer Treatment: The Rise of PD-1/PDL-1 and CTLA-4 as Key Therapeutic Targets.

Skin cancer is a significant health concern, affecting millions of individuals globally on an annual basis. According to data from the World Health Organization, it stands as the most prevalent form of cancer within the white population. Current treatments for skin cancer typically involve a combination of chemotherapy, radiation therapy, and surgery. However, these methods often come with drawbacks, such as side effects and potential scarring. Therefore, there is a growing need for alternative treatments that can offer effective results with fewer adverse effects, driving ongoing research in skin cancer therapy. The advancement of immune checkpoint inhibitors has been facilitated by a more profound comprehension of the interplay between tumors and the immune system, along with the regulatory mechanisms governing T-cells. As cancer treatment continues to evolve, immunotherapy is emerging as a powerful strategy, leading to a growing interest in the role of immunological checkpoints in skin cancer. Various types of immune checkpoints and their expression, including PD-1, PDL-1, CTLA-4, lymphocyte activation gene 3, and B7-H3, along with their blockers and monoclonal antibodies, have been established for various cancers. PD-1, PDL-1, and CTLA-4 are crucial immune system regulators, acting as brakes to prevent T-- cell overactivation and potential autoimmunity. However, tumors can exploit these checkpoints to evade immune detection. Inhibiting these immune checkpoints can enhance the body's ability to recognize and attack cancer cells. This review focuses on the characteristics of PD-1, PDL-1, and CTLA-4 immune checkpoints, their mechanism of action, and their role in skin cancer. Additionally, it summarizes the ongoing clinical trials sponsored or conducted by various pharmaceutical companies and provides insights into the latest patent data.

Investigation of the status of immune checkpoint molecules (PD-L1 and PD-1) in meningiomas by immunohistochemistry.

Meningiomas are the most common primary brain tumors of the central nervous system. Immunotherapy is a promising treatment method applied in many types of cancer. There is no standard and effective medical treatment to reduce recurrence and mortality in cases of incomplete resection of meningiomas and in high-grade cases. In order to investigate medical treatments in addition to surgery and radiotherapy, in this study, the status of immune checkpoint molecules (PD-L1/PD-1), which are the target of immunotherapy, in meningiomas was investigated. Four hundred two cases of meningioma diagnosed between 2007 and 2020 at our institution were used. New blocks were prepared from the appropriate blocks of the cases using the tissue microarray method. Sections obtained from these blocks were immunohistochemically stained with PD-1 and PD-L1 antibodies. Obtained data were interpreted with statistical analysis. Expression of PD-L1 was observed in 28.4% of meningiomas. Staining rates are higher in high-grade tumors. The staining rate of PD-L1 in the tumor increased significantly with pattern loss. PD-L1 expression in immune cells is 19.9%. Immune cell expression and the number of expressing immune cells correlate with spontaneous necrosis. Immune cell expression and the number of expressing immune cells are increased in high-grade meningiomas. PD-1 expression in immune cells is 9.0%, and this correlates with brain invasion. With these data, it was observed that the expression of immune checkpoint molecules PD-L1 and PD-1 increased especially in high-grade meningiomas. It may be the subject of research that these molecules may be targets of immunotherapy in the treatment of meningiomas.

Disulfidptosis-related long non-coding RNA signature predicts the prognosis, tumor microenvironment, immunotherapy, and antitumor drug options in colon adenocarcinoma.

This study aims to investigate the role and prognostic significance of long non-coding RNAs (lncRNAs) associated with disulfidptosis in colon adenocarcinoma (COAD). The TCGA database's clinical data and transcriptome profiles were employed. Analysis of previous studies identified 10 disulfidptosis-related genes (DRGs). We used these genes to construct a signature that could independently and accurately predict the prognosis of patients with COAD. The Kaplan-Meier (K-M) curve analysis showed that the lower-risk group had a better prognosis. With the help of multivariate Cox regression analysis, the risk score produced from the patient's signature might independently predict the outcomes. Utilizing a nomogram, the receiver operating characteristic (ROC) curve, and principal component analysis (PCA), the signature's predictive ability was also confirmed. It's interesting to note that immunotherapy, especially PD-1 immune checkpoint suppression, was more likely to benefit low-risk patients. The IC50 levels for certain anticancer agents were lower in the high-risk group. Finally, qRT-PCR analyses in colon cancer cell lines revealed elevated levels of lncRNAs CASC9, ZEB1-AS1, ATP2A1-AS1, SNHG7, AL683813.1, and AP003555.1, and reduced levels of FAM160A1-DT and AC112220.2, compared to normal cell lines. This signature offers insights into prognosis, tumor microenvironment, and options for immunotherapy and antitumor drugs in patients with COAD.

Integrated machine learning screened glutamine metabolism-associated biomarker SLC1A5 to predict immunotherapy response in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) stands as one of the most prevalent malignancies. While PD-1 immune checkpoint inhibitors have demonstrated promising therapeutic efficacy in HCC, not all patients exhibit a favorable response to these treatments. Glutamine is a crucial immune cell regulatory factor, and tumor cells exhibit glutamine dependence. In this study, HCC patients were divided into two subtypes (C1 and C2) based on glutamine metabolism-related genes via consensus clustering. The C1 pattern, in contrast to C2, was associated with a lower survival probability among HCC patients. Additionally, the C1 pattern exhibited higher proportions of patients with advanced tumor stages. The activity of C1 in glutamine metabolism and transport is significantly enhanced, while its oxidative phosphorylation activity is reduced. And, C1 was mainly involved in the progression-related pathway of HCC. Furthermore, C1 exhibited high levels of immunosuppressive cells, cytokine-receptor interactions and immune checkpoint genes, suggesting C1 as an immunosuppressive subtype. After stepwise selection based on integrated four machine learning methods, SLC1A5 was finally identified as the pivotal gene that distinguishes the subtypes. The expression of SLC1A5 was significantly positively correlated with immunosuppressive status. SLC1A5 showed the most significant correlation with macrophage infiltration, and this correlation was confirmed through the RNA-seq data of CLCA project and our cohort. Low-SLC1A5-expression samples had better immunogenicity and responsiveness to immunotherapy. As expected, SubMap and survival analysis indicated that individuals with low SLC1A5 expression were more responsive to anti-PD1 therapy. Collectively, this study categorized HCC patients based on glutamine metabolism-related genes and proposed two subclasses with different clinical traits, biological behavior, and immune status. Machine learning was utilized to identify the hub gene SLC1A5 for HCC classification, which also could predict immunotherapy response.

High expression of PDCD11 in colorectal cancer and its correlation with the prognosis and immune cell infiltration

ObjectiveTo undertake a comprehensive assay of PDCD11 expression in colorectal cancer (CRC) and its association with prognosis and immune cell infiltration (ICIN) utilizing bioinformatics tools. MethodsThe PDCD11 expression in CRC and pan-cancer was quantified through datasets from TCGA and GEO databases, and the assay was conducted through R software and the GEPIA database. Moreover, mRNA and protein expression data of PDCD11 were attained from the HPA database. It was attempted to establish protein-protein interaction networks of PDCD11 via the STRING and GeneMANIA databases. The association of PDCD11 expression with CRC staging was evaluated through R software, while its association with CRC and pan-cancer prognosis was figured out via the GEPIA database. Furthermore, the relationship of PDCD11 expression with ICIN was assayed using R software and the TIMER database. Additionally, the influences of PDCD11 knockdown on the proliferation, apoptosis, and migration of colon cancer RKO cell lines was evaluated. ResultsPDCD11 exhibited elevated expression in CRC and various other malignancies, potentially indicating a promotive role in cancer progression. Overexpression of PDCD11 was found to correlate with attenuated overall survival in CRC and other malignancies. Moreover, PDCD11 demonstrated promising predictive capabilities for distinguishing between tumor and non-tumor tissues. The positive association of high PDCD11 expression with the infiltration of neutrophils, dendritic cells, CD8+ T cells, CD4+ T cells, and macrophages, as well as with the expression of immune checkpoint molecules CTLA4 and PD-1 was noteworthy. Lentivirus-mediated PDCD11 knockdown suppressed RKO cell proliferation, colony formation, and migration, while triggered apoptosis in these cells. ConclusionThe outcomes unveiled the noticeable function of PDCD11 in CRC and various other malignancies, emphasizing its potential as a prognostic biomarker and therapeutic target.

Adverse Events of PD-1, PD-L1, CTLA-4, and LAG-3 Immune Checkpoint Inhibitors: An Analysis of the FDA Adverse Events Database.

This study aimed to identify the 25 most prevalent adverse events (AEs) associated with FDA-approved immune checkpoint inhibitors (ICIs)-specifically, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors-using data from the FDA Adverse Events Reporting System (FAERS), a publicly available repository of reported drug adverse events, and AERSMine, an open-access pharmacovigilance tool, to investigate these adverse events. For PD-1 inhibitors, the most common AEs were diarrhea, fatigue, and pyrexia, with notable instances of neutropenia and hypothyroidism, particularly with toripalimab and dostarlimab. PD-L1 inhibitors also frequently caused pyrexia, diarrhea, and fatigue, with interstitial lung disease and hypothyroidism showing a class effect, and drug-specific AEs such as hepatotoxicity and chills. CTLA-4 inhibitors predominantly resulted in diarrhea and colitis, with ipilimumab frequently causing pyrexia and rash, while tremelimumab exhibited unique AEs such as biliary tract infection. The LAG-3 inhibitor relatlimab reported fewer AEs, including pyrexia and pneumonia. Rare but significant AEs across all inhibitors included myocarditis and myasthenia gravis. This study provides a detailed overview of the 25 most common AEs associated with ICIs, offering valuable insights for clinical decision-making and AE management. Further research is necessary to elucidate the mechanisms underlying these AEs and to develop targeted interventions to enhance the safety and efficacy of ICI therapy in patients with cancer.

Acute natural killer cells response to a continuous moderate intensity and a work-matched high intensity interval exercise session in metastatic cancer patients treated with chemotherapy

BackgroundIt has been suggested that the acute natural killer (NK) cell response to aerobic exercise might contribute to the tumor suppressor effect of regular exercise observed in preclinical studies. Moreover, because this response is modulated by exercise intensity, high-intensity intervals exercise (HIIE) might represent an interesting therapeutic approach in cancer patients. However, this immune response remains unstudied in cancer patients currently undergoing chemotherapy. ObjectiveTo characterize the acute NK cell response following a moderate-intensity continuous aerobic exercise session (MOD), and a HIIE session in metastatic cancer patients treated with chemotherapy. MethodsTwelve cancer patients (45–65 years old) underwent a MOD and a duration and work-matched HIIE trial, in a block-randomized order. Peripheral blood mononuclear cells (PBMC) were isolated before, after and 1h after each trial. NK cell subsets were enumerated using flow cytometry and complete blood counts. The surface expression of the cytotoxic NK cell (cNK; CD56dimCD16+) subset was evaluated for its expression of the differentiation markers CD57 and CD158a, the activating receptor NKG2D, the immune checkpoints TIM-3 and PD-1, and the chemokine receptors CXCR3, CXCR4 and CCR2. ResultscNK cell blood counts increased immediately following MOD (p < 0.001) and decreased back to pre-exercise values 1 h after exercise cessation (p < 0.001). The most responsive cNK cell subsets were expressing CD57, CD158a, NKG2D, TIM-3 and CXCR3. The HIIE trial elicited a similar biphasic response, without any difference between trials (all p ≥ 0.38). However, significant changes in the MFI values of CXCR4 and NKG2D were observed in the cNK cell subset following HIIE (all p ≤ 0.038), but not MOD. ConclusionIn metastatic cancer patients undergoing chemotherapy, both MOD and HIIE can elicit an acute mobilisation and egress of NK cells exhibiting phenotypic characteristics associated with high cytotoxicity and tumor homing. Future longitudinal trials are needed to determine if combining aerobic exercise training and chemotherapy will translate towards favorable immune and clinical outcomes.

Lactylated Apolipoprotein C-II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis.

Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.

TRP-2 / gp100 DNA vaccine and PD-1 checkpoint blockade combination for the treatment of intracranial tumors

Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these intracranial tumors due to relatively low toxicity and tumor specificity. Here we show that SCIB1, a TRP-2 and gp100 directed ImmunoBody® DNA vaccine, generates a strong TRP-2 specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced and the detection of a significant number of pentamer positive T cells in the spleen of vaccinated mice. Furthermore, vaccine-induced T cells were able to recognize and kill B16HHDII/DR1 cells after a short in vitro culture. Having found that glioblastoma multiforme (GBM) expresses significant levels of PD-L1 and IDO1, with PD-L1 correlating with poorer survival in patients with the mesenchymal subtype of GBM, we decided to combine SCIB1 ImmunoBody® with PD-1 immune checkpoint blockade to treat mice harboring intracranial tumors expressing TRP-2 and gp100. Time-to-death was significantly prolonged, and this correlated with increased CD4+ and CD8+ T cell infiltration in the tissue microenvironment (TME). However, in addition to PD-L1 and IDO, the GBM TME was found to contain a significant number of immunoregulatory T (Treg) cell-associated transcripts, and the presence of such cells is likely to significantly affect clinical outcome unless also tackled.

Integrative Pan-Cancer Analysis Reveals the Oncogenic Role of MND1 and Validation of MND1's Role in Breast Cancer.

Meiotic nuclear division 1 (MND1) is a meiosis-specific protein that promotes lung adenocarcinoma progression. However, its expression and biological function across cancers remain largely unexplored. The expression, prognostic significance, mutation status, and methylation profile of MND1 in various cancers were comprehensively analyzed using the TIMER, GTEX, Kaplan-Meier plotter, cBioPortal, and GSCA databases. Additionally, we constructed a PPI network, enrichment analysis and single-cell transcriptomic sequencing to elucidate the underlying mechanism of MND1. Furthermore, we investigated the association between MND1 expression and drug sensitivity using CellMiner. Moreover, we also explored the correlation between MND1 expression and immune infiltration. Finally, we validated the functional role of MND1 in breast cancer through IHC staining, CCK8, EdU, colony formation, and flow cytometry assays. MND1 has been reported to be highly expressed in Pan-cancer, High MND1 expression was significantly associated with poor prognosis in cancers. Additionally, MND1 mutation frequency is high in most cancers, and its expression correlates with methylation. Furthermore, MND1 expression significantly correlates with immune checkpoint blockade (ICB) markers, including PD-L1, PD-1, and CTLA-4. The PPI network reveals interactions between MND1 and PSMC3IP, BRCA1, and BRCA2. Enrichment analysis and single-cell sequencing indicate that MND1 positively correlates with cell cycle. ROC curve reveals favorable diagnostic efficacy of MND1 in breast cancer. In vitro, MND1 overexpression promotes breast cancer cell proliferation and increases the expression of key cell cycle regulators (CDK4, CDK6, and cyclin D3), accelerating the G1/S phase transition and leading to abnormal breast cancer cell proliferation. The immunohistochemical analysis revealed a robust expression of MND1 in breast cancer tissues, exhibiting a significant positive correlation with PD-L1 and FOXP3. MND1 is an oncogene and may serve as a biomarker for cancer prognosis and immunotherapy. Targeting MND1 may be a potential tumor treatment strategy.

Characterization of Immune Infiltrate Along the Leading Edge of Differentiated Thyroid Cancer.

Background: Although the impact of tumor-immune infiltrate has been reported on differentiated thyroid cancer (DTC) behavior, the expression of immune checkpoints [programmed cell death protein 1 (PD-1) and its ligand (PD-L1)] alone has not been able to predict response to immunotherapies. We aimed to identify tumor-infiltrating immune cells and checkpoints associated with DTC. Methods: We performed multiplex immunofluorescence on deparaffinized thyroid tissue collected at thyroidectomy from 17 adults with DTC to characterize the tumor immune microenvironment for leukocytes (CD45+), T cells (CD3+), T regulatory cells (Tregs) (CD3+FOXP3+), CD4+ T cells (CD3+CD4+), CD8+ T cells (CD3+CD8+), macrophages (CD68+), M2 macrophages (CD68+CD163+), M1 Macrophages (CD68+ inducible nitric oxide synthase [iNOS]+), and immune checkpoints PD-1 and PD-L1. We compared the mean percentage expression of immune markers between tumor and adjacent thyroid tissue from the same patient by paired t-test and performed spatial analysis along the tumor's leading edge. Results: Immune checkpoints PD-1 and PD-L1 showed a significant increase in expression intratumorally as compared to adjacent thyroid tissue (p < 0.05). A higher trend for M2 macrophages was observed intratumorally compared to adjacent tissue. Along the leading edge, PD-L1 expression correlated negatively with CD45 and positively with CD163 intratumorally. On exploratory analysis, there was a nonsignificant trend for higher FOXP3 but less CD8 and iNOS expression in tumor from DTC with (n = 3) versus without distant metastases (n = 14). There was a nonsignificant trend for higher CD58 and iNOS expression in DTC with (n = 7) than without thyroiditis (n = 10). Conclusions: Higher tumoral PD-1 and PD-L1 expression indicate their role in DTC occurrence. A trend for more Tregs and M2 macrophages but less M1 macrophages intratumorally in patients with distant metastatic DTC, suggests their potential role as prognostic biomarkers. Future studies with larger sample sizes are needed to compare various clinicopathologic severities to harness tumor microenvironment for cancer prognostication and therapy.

IL-6 Inhibition as a Therapeutic Target in Aged Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which there are currently no effective disease-modifying treatments. Immunosenescence is associated with the production of the senescence-associated secretory phenotype (SASP), with IL-6 being one of the most prominent cytokines. IL-6 is a determinant for the development of autoimmunity and neuroinflammation and is involved in the pathogenesis of MS. Herein, we aimed to preclinically test the therapeutic inhibition of IL-6 signaling in experimental autoimmune encephalomyelitis (EAE) as a potential age-specific treatment for elderly MS patients. Young and aged mice were immunized with myelin oligodendrocyte protein (MOG)35-55 and examined daily for neurological signs. Mice were randomized and treated with anti-IL-6 antibody. Inflammatory infiltration was evaluated in the spinal cord and the peripheral immune response was studied. The blockade of IL-6 signaling did not improve the clinical course of EAE in an aging context. However, IL-6 inhibition was associated with an increase in the peripheral immunosuppressive response as follows: a higher frequency of CD4 T cells producing IL-10, and increased frequency of inhibitory immune check points PD-1 and Tim-3 on CD4+ T cells and Lag-3 and Tim-3 on CD8+ T cells. Our results open the window to further studies aimed to adjust the anti-IL-6 treatment conditions to tailor an effective age-specific therapy for elderly MS patients.

Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function

Targeting immune checkpoint receptors on T cells is a common cancer treatment strategy. Frequently, this is accomplished through antibodies targeting the ligand of inhibitory co-receptors. Blocking the immune checkpoint PD-1 binding to its ligands PD-L1 and PD-L2 prevents downstream signaling and enhances anti-tumor T cell responses. This approach improved cancer patients’ outcomes. However, only one-third of the patients respond to these treatments. To better understand the mechanism of anti-PD-1 antibodies, we explored the location of PD-1 within the immune synapse. Surprisingly, we discovered that anti-PD-1 antibodies, besides blocking the interaction between PD-1 and its ligands, also removed PD-1 from the synapse. We demonstrated a correlation between removing PD-1 from the synapse by anti-PD-1 antibodies and the extent of T cell activation.