Programmed Death Ligand-1 Pathway Research Articles

Advances in immunotherapy of M2 macrophages and gastrointestinal stromal tumor.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal-derived tumors of the GI tract. They can occur throughout the GI tract, and the survival time of some patients can be improved by first-line targeted therapy with imatinib. However, there are some limitations with imatinib treatment. Immunotherapy for GIST has attracted much attention in recent years, and as one of the most abundant cells in the GIST microenvironment, M2 macrophages play an important role in disease progression. They have unique anti-inflammatory and pro-tumorigenic effects and are one target for immunotherapy. This review summarizes the connection between different factors and the programmed death receptor-1/programmed death ligand-1 pathway and M2 macrophages to reactivate or enhance anti-tumor immunity and improve imatinib efficacy, and to provide new ideas for GIST immunotherapy.

Construction of Hierarchically Biomimetic Iron Oxide Nanosystems for Macrophage Repolarization-Promoted Immune Checkpoint Blockade of Cancer Immunotherapy.

Cancer immunotherapy is developing as the mainstream strategy for treatment of cancer. However, the interaction between the programmed cell death protein-1 (PD-1) and the programmed death ligand 1 (PD-L1) restricts T cell proliferation, resulting in the immune escape of tumor cells. Recently, immune checkpoint inhibitor therapy has achieved clinical success in tumor treatment through blocking the PD-1/PD-L1 checkpoint pathway. However, the presence of M2 tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) will inhibit antitumor immune responses and facilitate tumor growth, which can weaken the effectiveness of immune checkpoint inhibitor therapy. The repolarization of M2 TAMs into M1 TAMs can induce the immune response to secrete proinflammatory factors and active T cells to attack tumor cells. Herein, hollow iron oxide (Fe3O4) nanoparticles (NPs) were prepared for reprogramming M2 TAMs into M1 TAMs. BMS-202, a small-molecule PD-1/PD-L1 inhibitor that has a lower price, higher stability, lower immunogenicity, and higher tumor penetration ability compared with antibodies, was loaded together with pH-sensitive NaHCO3 inside hollow Fe3O4 NPs, followed by wrapping with macrophage membranes. The formed biomimetic FBN@M could produce gaseous carbon dioxide (CO2) from NaHCO3 in response to the acidic TME, breaking up the macrophage membranes to release BMS-202. A series of in vitro and in vivo assessments revealed that FBN@M could reprogram M2 TAMs into M1 TAMs and block the PD-1/PD-L1 pathway, which eventually induced T cell activation and the secretion of TNF-α and IFN-γ to kill the tumor cells. FBN@M has shown a significant immunotherapeutic efficacy for tumor treatment.

A novel bispecific peptide targeting PD-1 and PD-L1 with combined antitumor activity of T-cells derived from the patients with TSCC

Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are key immune checkpoints (ICs) that critically influence immunotherapy. Tumor resistance to single IC-targeting drugs has increased interest in dual-target drugs, which have shown feasibility for cancer treatment. In this study, we aimed to develop dual-target peptide drugs targeting the PD-1/PD-L1 pathway and to evaluate their efficacy compared to functional antibodies in enhancing the cytotoxicity of human T cells against tongue squamous carcinoma cell lines. Through sequence analysis and peptide truncation, we modified a pre-existing peptide named nABPD-1 targeting PD-1. Subsequently, we obtained two novel peptides named nABPD-2 and nABPD-3, with nABPD-2 showing an enhanced affinity for human PD-1 protein compared to nABPD-1. Importantly, nABPD-2 exhibited dual-targeting capability, possessing a high affinity for both PD-L1 and PD-1. Furthermore, nABPD-2 effectively promoted the cytotoxicity of human T cells against tongue squamous carcinoma cell lines, surpassing the efficacy of anti-PD-1 or anti-PD-L1 functional antibodies alone. Considering that nABPD-2 has lower production costs and dose requirements, it can potentially be used in therapeutic applications.

HBeAg induces neutrophils activation impairing NK cells function in patients with chronic hepatitis B.

The role of neutrophils in hepatitis B virus (HBV) infection has been a subject of debate due to their involvement in antiviral responses and immune regulation. This study aimed to elucidate the neutrophil characteristics in patients with chronic hepatitis B (CHB). Through flow cytometry and ribonucleic acid-sequencing analysis, the phenotypes and counts of neutrophils were analyzed in patients with CHB. Moreover, the effects of HBeAg on neutrophils and the corresponding pattern recognition receptors were identified. Simultaneously, the cross-talk between neutrophils and natural killer (NK) cells was investigated. Neutrophils were activated in patients with CHB, characterized by higher expression levels of programmed death-ligand 1 (PD-L1), cluster of differentiation 86, and interleukin-8, and lower levels of CXC motif chemokine receptor (CXCR) 1 and CXCR2. Hepatitis B e antigen (HBeAg) partially induces neutrophil activation through the Toll-like receptor 2 (TLR2). A consistent upregulation of the TLR2 and HBeAg expression was observed in patients with CHB. Notably, the genes encoding molecules pivotal for NK-cell function upon NK receptor engagement enriched in neutrophils after HBeAg activation. The HBeAg-activated neutrophils demonstrated the ability to decrease the production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in NK cells, while the PD-1 and PD-L1 pathways partially mediated the immunosuppression. The immunosuppression of neutrophils induced by HBeAg suggests a novel pathogenic mechanism contributing to immune tolerance in patients with CHB.

Lymphocytes in Patients with Chronic Active Epstein-Barr Virus Disease Exhibited Elevated PD-1/PD-L1 Expression and a Prevailing Th2 Immune Response.

Chronic active Epstein-Barr virus disease (CAEBV) is a proliferative disease of EBV+ T or natural killer (NK) cells with an unclear pathogenesis. This study aimed to examine the frequency and exhaustion levels of lymphocyte subsets in patients with CAEBV to further investigate the pathogenesis. Using flow cytometry, we detected the frequency, expression levels of programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1), and EBV infection status of peripheral T subsets and NK cells in patients with CAEBV and healthy individuals. 24 patients and 15 healthy individuals were enrolled in this study. Patients showed notably higher expression levels of PD-1 and PD-L1 in peripheral T subsets and NK cells compared to healthy individuals (P < 0.05). EBV+ lymphocytes exhibited significantly higher PD-L1 expression levels than EBV- lymphocytes. Additionally, the frequency of effector memory T (Tem) cells was significantly increased in patients, and the PD-L1 expression level was positively correlated with the EBV load. Besides, helper T cell 2 (Th2) immune bias, also favoring EBV amplification, was found in patients, including increased Th2 cell frequency, enhanced response capacity, and elevated serum levels of associated cytokines. The distribution and PD-1 expression levels of peripheral T subsets returned to normal in patients who responded to PD-1 blockade therapy. The up-regulation of the PD-1/PD-L1 pathway of peripheral T and NK cells and Th2 immune predominance jointly promoted EBV replication and the development of CAEBV. PD-1 blockade therapy reduced the PD-1 expression level of lymphocytes and helped normalize the distribution of the T subsets.

PRRX1 upregulates PD-L1 in human mesenchymal stem cells.

Mesenchymal stem cells (MSCs) have been demonstrated to be efficacious in clinical applications for the amelioration of immune disorders, including graft-versus-host disease (GvHD) and Crohn's disease. The immunosuppressive role of Programmed death-ligand 1 (PD-L1) in MSCs is pivotal, yet the regulatory mechanisms governing its expression remain to be fully elucidated. In this study, we explored the influence of paired-related homeobox (PRRX1), a determinant of multipotency and self-renewal in MSCs, on the expression of various surface antigens, notably PD-L1. Multiple isoforms of PRRX1 were found to augment the mRNA levels of MSC markers, such as CD26 and CD317, with all isoforms elevating PD-L1 expression at both mRNA and protein levels. This study reveals that PRRX1 may act as a potential immunomodulatory factor in MSCs by regulating the PD-L1 pathway.

HMGB1 promotes neutrophil PD-L1 expression through TLR2 and mediates T cell apoptosis leading to immunosuppression in sepsis

Neutrophils and T lymphocytes are closely related to occurrence of immunosuppression in sepsis. Studies have shown that neutrophil apoptosis decreases and T lymphocyte apoptosis increases in sepsis immunosuppression, but the specific mechanism involved remains unclear. In the present study, we found Toll-like Receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) were significantly activated in bone marrow neutrophils of wild-type mice after LPS treatment and that they were attenuated by treatment with C29, an inhibitor of TLR2. PD-L1 activation inhibits neutrophil apoptosis, whereas programmed death protein 1 (PD-1)activation promotes apoptosis of T lymphocytes, which leads to immunosuppression. Mechanistically, when sepsis occurs, pro-inflammatory factors and High mobility group box-1 protein (HMGB1) passively released from dead cells cause the up-regulation of PD-L1 through TLR2 on neutrophils. The binding of PD-L1 and PD-1 on T lymphocytes leads to increased apoptosis of T lymphocytes and immune dysfunction, eventually resulting in the occurrence of sepsis immunosuppression. In vivo experiments showed that the HMGB1 inhibitor glycyrrhizic acid (GA) and the TLR2 inhibitor C29 could inhibit the HMGB1/TLR2/PD-L1 pathway, and improving sepsis-induced lung injury. In summary, this study shows that HMGB1 regulates PD-L1 and PD-1 signaling pathways through TLR2, which leads to immunosuppression.

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy.

Immunotherapy has been developed, which harnesses and enhances the innate powers of the immune system to fight disease, particularly cancer. PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) are key components in the regulation of the immune system, particularly in the context of cancer immunotherapy. PD-1 and PD-L1 are regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation and glycosylation. PROTACs (Proteolysis Targeting Chimeras) are a type of new drug design technology. They are specifically engineered molecules that target specific proteins within a cell for degradation. PROTACs have been designed and demonstrated their inhibitory activity against the PD-1/PD-L1 pathway, and showed their ability to degrade PD-1/PD-L1 proteins. In this review, we describe how PROTACs target PD-1 and PD-L1 proteins to improve the efficacy of immunotherapy. PROTACs could be a novel strategy to combine with radiotherapy, chemotherapy and immunotherapy for cancer patients.

Blocking senescence and tolerogenic function of dendritic cells induced by γδ Treg cells enhances tumor-specific immunity for cancer immunotherapy

BackgroundRegulatory T (Treg) cells are a key component in maintaining the suppressive tumor microenvironment and immune suppression in different types of cancers. A precise understanding of the molecular mechanisms used...

Programmed Death Ligand 1: Unveiling its Impact on Endometrial Carcinogenesis.

Endometrial cancer is a commonly diagnosed gynecological malignancy presenting an increasing incidence worldwide. The immune response plays a crucial role in the mechanisms underlying carcinogenesis and the progression of tumors. In recent times, there has been a discernible surge in the acknowledgment of the importance of programmed death ligand 1 (PDL1) in evading the immunological response of the host and promoting the growth of malignancies. The primary aim of this review is to consolidate the existing corpus of evidence pertaining to the role of PDL1 in the etiology and progression of endometrial cancer and investigate the molecular mechanisms involved in the expression of PDL1 in cells impacted by endometrial cancer. Finally, the association between PDL1 expression and clinical outcomes, as well as the potential therapeutic uses of targeting the PDL1 pathway are being analyzed.

Exosomal circ_0032704 confers sorafenib resistance to hepatocellular carcinoma and contributes to cancer malignant progression by modulating the miR-514a-3p/PD-L1 pathway.

This study aims to explore the role of circ_0032704 in sorafenib-resistant hepatocellular carcinoma (HCC). The expression of circ_0032704, miR-514a-3p, and programmed death-ligand 1 (PD-L1) mRNA was detected by quantitative real-time PCR (qPCR). The expression of multidrug resistant-related proteins, migration/invasion-related proteins, exosome-related proteins, and PD-L1 protein was detected by western blot. Cell viability was detected by CCK-8 assay. Cell proliferation, migration, and invasion were assessed by EdU assay, wound healing assay, and transwell assay. The binding between miR-514a-3p and circ_0032704 or PD-L1 was verified by RIP assay, pull-down assay, and dual-luciferase reporter assay. Cell- or serum-derived exosomes were isolated and identified by TEM and NTA. Xenograft models were established to determine the effect of circ_0032704 on drug resistance invivo. Circ_0032704 was overexpressed in sorafenib-resistant HCC tissues and cells. Circ_0032704 knockdown reduced sorafenib resistance in HCC cells and inhibited cell proliferation, migration, and invasion of sorafenib-resistant HCC cells, while these effects were reversed by PD-L1 overexpression. We found that circ_0032704 positively regulated PD-L1 expression via targeting miR-514a-3p. Exosomes with circ_0032704 inhibition reduced sorafenib resistance in HCC cells and inhibited cell proliferation, migration, and invasion of sorafenib-resistant HCC cells. Exosomes with circ_0032704 inhibition also inhibited tumor growth invivo. The expression of circ_0032704 in exosomes was stable and possessed diagnostic value. Circ_0032704 enhanced sorafenib resistance in HCC and promoted the malignant development of sorafenib-resistant HCC. Circ_0032704 could be transported by exosomes, and exosomal circ_0032704 had diagnostic value.

Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway.

To investigate the therapeutic effects and immunomodulatory mechanisms of human placenta-derived mesenchymal stem cells (PMSCs) in diabetic kidney disease (DKD). Streptozotocin-induced DKD rats were administered an equivalent volume of saline or PMSCs (1 × 106 in 2 mL phosphate-buffered saline per rat) for 3 weeks. Eight weeks after treatment, we examined the biochemical parameters in the blood and urine, the ratio of T helper 17 cells (Th17) and regulatory T cells (Treg) in the blood, cytokine levels in the kidney and blood, and renal histopathological changes. In addition, we performed PMSC tracing and renal transcriptomic analyses using RNA-sequencing. Finally, we determined whether PMSCs modulated the Th17/Treg balance by upregulating programmed death 1 (PD-1) in vitro. The PMSCs significantly improved renal function, which was assessed by serum creatinine levels, urea nitrogen, cystatin C levels, urinary albumin-creatinine ratio, and the kidney index. Further, PMSCs alleviated pathological changes, including tubular vacuolar degeneration, mesangial matrix expansion, and glomerular filtration barrier injury. In the DKD rats in our study, PMSCs were mainly recruited to immune organs, rather than to the kidney or pancreas. PMSCs markedly promoted the Th17/Treg balance and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-17A and IL-1β) in the kidney and blood of DKD rats. In vitro experiments showed that PMSCs significantly reduced the proportion of Th17 cells and increased the proportion of Treg cells by upregulating PD-1 in a cell-cell contact manner and downregulating programmed death-ligand 1 (PD-L1) expression in PMSCs, which reversed the Th17/Treg balance. We found that PMSCs improved renal function and pathological damage in DKD rats and modulated Th17/Treg balance through the PD-1/PD-L1 pathway. These findings provide a novel mechanism and basis for the clinical use of PMSCs in the treatment of DKD.

PD-L1 and PD-1 expression in pediatric post-transplant Burkitt lymphoma and other monomorphic post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLD) develop as a consequence of immune suppression. Programmed death protein 1 (PD-1), a regulator of host immune activation, binds to programmed death-ligand 1 (PD-L1) to suppress the T-cell immune response. PD-1/PD-L1 pathway may play a role in PTLD. The objective was to describe intratumoral expression of PD-L1 and PD-1 in pediatric monomorphic PTLD, and assess if density of these cells is associated with progression-free survival (PFS) and overall survival (OS). Clinical variables and outcome data were collected on B-cell monomorphic PTLD treated in Toronto, Canada between 2000 and 2017. Diagnostic area from tumor tissue was identified to count CD3-positive or PD-1-positive cells and CD3-negative lymphoma B cells or PD-L1-positive cells. CD3+ , PD-1+ , and PD-L1+ cell densities were compared between cases of PTLD. OS and PFS were analyzed. We identified 25 cases of B-cell monomorphic PTLD; majority Burkitt lymphoma (32%) and diffuse large B-cell lymphoma (56%). All cases had CD3+ cells infiltrating the tumor, and median percentage of CD3+ cells was 14% (interquartile range: 6.2%-25%). Twelve cases (48%) had PD-1+ cell infiltrating (range: 1%-83%) and 13 cases (52%) had no PD-1+ cells infiltrating. Sixteen cases (64%) had PD-L1+ cells present; however, there was no PD-L1 expression on any Burkitt lymphoma tissue. When comparing PD-1 and PD-L1 expression, there was no difference in OS or PFS. Intratumoral presence of PD-1+ and PD-L1+ cells varied in pediatric patients with monomorphic PTLD; however, no relationship to OS and PFS was identified.

Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

Dual-modulation of immunosuppressive pathways using sono-activatable semiconducting polymer nanofeedbacks for cancer immunotherapy

Although the combinations of immunotherapy with other therapies can offer promising possibility to sensitize tumors to various immunotherapeutic strategies for amplified antitumor immune responses, the up-regulations of immunosuppressive pathways after cancer treatments still greatly compromise the therapeutic outcomes. Herein, we report the dual-modulation of up-regulated immunosuppressive pathways by designing sono-activatable semiconducting polymer nanofeedbacks (SPNSA) for cancer immunotherapy. The SPNSA are constructed to contain semiconducting polymer nanoparticles (SPNs) as the sonosensitizers, adenosine receptor A2A antagonist (SCH58261), programmed death-ligand 1 (PD-L1) antibody (aPD-L1) and singlet oxygen (1O2)-cleavable linkers. Upon ultrasound (US) irradiation, the SPNs produce 1O2 for sonodynamic therapy (SDT) and inducing immunogenic cell death (ICD) with up-regulations of adenosine level and PD-L1 expression. In addition, the produced 1O2 can snip the 1O2-cleavable linkers for on-demand release of SCH58261 and aPD-L1 that act as the feedbacks to modulate the up-regulated immunosuppressive adenosine and PD-L1 pathways simultaneously, resulting in further amplified antitumor immunological effect. In the bilateral tumor-bearing mouse models, the administration of SPNSA and sono-activation can greatly inhibit the tumor growths and metastasis. This study thus provides a sono-activatable nanoplatform for precisely amplifying immunotherapeutic effect via feedback modulating of immunosuppressive pathways post-treatments.

Comprehensive Review: Unveiling the Pro-Oncogenic Roles of IL-1ß and PD-1/PD-L1 in NSCLC Development and Targeting Their Pathways for Clinical Management.

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. Recent advancements in our understanding of the intricate relationship between inflammation and oncogenesis, particularly involving the IL-1β/PD-1/PD-L1 pathway, have shed light on their application in lung cancer development and clinical outcomes of patients. Targeting these pathways in cancers like NSCLC holds immense potential to revolutionize cancer treatment, particularly for patients lacking targetable genetic mutations. However, despite these promising prospects, there remain certain aspects of this pathway that require further investigation, particularly regarding treatment resistance. Therefore, the objective of this review is to delve into the role of IL-1β in NSCLC, its participation in inflammatory pathways, and its intricate crosstalk with the PD-1/PD-L1 pathway. Additionally, we aim to explore the potential of IL-1β as a therapeutic target for NSCLC treatment.

Expression of Programmed Death Ligand 1 (PD-L1) in Breast Cancer patients in India and its Correlation with Prognostic Parameters

Background: The PD-1/PD-L1 pathway represents an adaptive immune resistance mechanism that is exerted by tumor cells. The study was conducted to evaluate the expression of PD-L1 in breast carcinoma in India and to find out its correlation with prognostic parameters. Despite numerous studies, there is a lack of literature for such studies in Indian patients. Moreover, the results obtained from these studies have not been uniform. Methods: A hospital-based cross-sectional study was conducted on 150 cases of breast carcinoma. The invasive cancer specimens were assessed for routine microscopy and classified into various histopathological subtypes. Bloom Richardson grading was done. Immunohistochemistry for surrogate molecular classification as well as PD-L1 was performed. PD-L1 expression was then compared with several prognostic parameters such as tumor subtype, tumor grade, surrogate molecular classification and pTNM stage. Data analysis was done using Statistical Package for Social Sciences (SPSS) version 21.0. A P value of &lt;0.05 was considered statistically significant. Results: PD-L1 was positive in 14.67% of patients with score 1 in 6% and score 2 in 8.67% of patients. The PD-L1 expression showed a positive correlation with the tumor of higher grades (grade3). It was significantly higher among IBC with medullary features as compared to IBC-NST, IBC with papillary features and the Lobular type. PD-L1 showed a significant association with surrogate molecular classification as well. Its expression was found to be the highest in Triple negative breast cancer subtype as compared to tumors showing ER/PR positivity (p&lt;0.05). However, there was no significant association between PD-L1 and TNM staging. Conclusion: This study revealed a significant association between PD-L1 several prognostic factors such as higher tumor grade (grade3), Triple Negative breast cancer, and IBC with the medullary pattern subtype. The association between PD-L1 and such prognostic parameters signifies its role in tumor mechanism and makes it a potential target for immunotherapy especially in Triple Negative breast cancer cases which lack specific targeted therapies. Moreover, paucity of literature on PD-L1 in breast cancer patients in India and the data showing conflicting results make this study valuable. Our study shall be helpful in further adding to the knowledge of PD-L1 expression in breast cancer especially in Indian women.

Combining histological grade, TILs, and the PD-1/PD-L1 pathway to identify immunogenic tumors and de-escalate radiotherapy in early breast cancer: a secondary analysis of a randomized clinical trial

BackgroundThe implementation of immunological biomarkers for radiotherapy (RT) individualization in breast cancer requires consideration of tumor-intrinsic factors. This study aimed to investigate whether the integration of histological grade, tumor-infiltrating lymphocytes...

PD-L1 and HLA-class I expression status and their therapeutic implication in oesophageal small-cell carcinoma.

Oesophageal small-cell carcinoma is a rare and highly aggressive subtype of oesophageal cancer with a dismal prognosis. To explore the potential applicability of immunotherapy, we investigated the expression status of programmed death ligand 1 (PD-L1) and human leukocyte antigen (HLA)-class I and the degree of tumour-infiltrating lymphocytes (TILs) in oesophageal small-cell carcinoma. PD-L1 and HLA-class I expression levels were evaluated in 10 pure small-cell carcinomas and five mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). The combined positive score (CPS) and tumour proportion score (TPS) were used for PD-L1 assessment. Immunohistochemistry for mismatch repair (MMR) proteins was also performed. PD-L1 immunohistochemistry demonstrated CPS ≥1 in nine (60%), CPS ≥10 in five (33%), and TPS ≥1 in five (33%) cases. Overall survival was significantly longer in patients with CPS ≥1 than in those with CPS <1. HLA-class I deficiency (>50% tumour cells) was noted in five cases (33%), with no significant correlation with PD-L1 expression status. Among the five MiNENs, HLA-class I expression was decreased in the small-cell carcinoma component of three cases. HLA-class I deficiency was significantly associated with higher TNM stage and reduced TIL levels. MMR deficiency was not observed in any case. Given that a significant subset (40%) exhibited PD-L1 CPS ≥1 with preserved HLA-class I expression and high levels of TIL, the PD-1/PD-L1 pathway is a potential therapeutic target for oesophageal small-cell carcinoma.

Abstract 5087: Combination therapy of immune checkpoint inhibitor and HIF1α/c-MET peptide vaccine suppresses metastasis by modulating tumor microenvironment in triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) accounts for 20% of all breast cancer and has limited therapeutic option except for immunotherapy because ER, PR, and HER2 targeted for treatment are absent. It also tends to be more aggressive meaning more likely to metastasize faster to other organs such as lungs, liver, and bone, and its recurrence rate is high which leads to a poor prognosis. Immunotherapy is an option to treat TNBC such as programmed death ligand 1 (PD-L1) antibody. However, tumor cells use various immune evasion mechanisms in addition to PD-1/PD-L1 pathway to interrupt the effect of immunotherapy. Moreover, tumor microenvironment (TME) is one of the important factors for the effective anti-tumor immune responses from immunotherapy. Hypoxia is a typical event in TNBC. Hypoxia inducible factor 1-alpha (HIF1α) is a transcription factor that regulates angiogenesis by expressing VEGF, and in addition, upregulates the c-MET which increases the proliferation, migration, and survival of tumor cells. Moreover, HIF1α directly regulates the expression of CD47. CD47 is a transmembrane protein that binds to SIRPα of macrophages to inhibit the phagocytosis of macrophages. Therefore, the efficacy of immune checkpoint inhibitors decreases even if there is a higher degree of tumor-infiltrating lymphocytes (TILs). Combination therapy with immune checkpoint and tumor associated antigens (TAAs) derived peptide vaccine could inhibit metastasis. In present study, we found that HIF1α/c-MET peptide vaccination delayed metastasis in C3(1)Tag mouse. We also investigated whether combination therapy with immune checkpoint inhibitors and peptide vaccine inhibited metastasis. Next, we observed that combination strategy of HIF1α/c-MET peptide vaccine and treated anti-PD-L1 antibody or/and anti-CD47 antibody was more effective in systemically inoculated M6 cells growth in C3(1)Tag mice. Immunohistochemical analysis of the tumors showed that the protein expression of CD47, HIF1α, and c-MET were significantly decreased. On the other hand, CD4+ T cells, CD8+ T cells and M1 macrophages increased, but M2 macrophages decreased, resulting in delayed metastasis in combination therapy group compared to single therapy and control group. In addition, IFNγ ELISPOT showed that peptide vaccination significantly increased the HIF1α/c-MET specific IFNγ-secreting T cell response in splenocytes. We also assessed osteoclastogenesis in bones, which showed reduction of osteoclast in combination therapy group compared to single therapy and control group.Taken together, combination therapy with immune checkpoint inhibitor targeting PD-L1 and CD47 and peptide vaccine appears to be a promising strategy that inhibit metastasis by modulating tumor microenvironment in triple negative breast cancer. Citation Format: JinHwa Hong, Jimin Lee, Soon Young Lim, Ju Won Kim, Ah Reum Lim, Kyong Hwa Park. Combination therapy of immune checkpoint inhibitor and HIF1α/c-MET peptide vaccine suppresses metastasis by modulating tumor microenvironment in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5087.