Immunomedicine最新文献

Antibodies to programmed cell death protein 1 (anti-PD-1) have become a promising immunotherapy for triple negative breast cancer (TNBC), blocking PD-L1 signaling from pro-tumor cells through T cell PD-1 receptor binding. Nevertheless, only 10%–20% of PD-L1⁺ metastatic TNBC patients who meet criteria benefit from immune checkpoint blockade (ICB), and biomarkers to predict patient response have been elusive. We have previously developed an immunological niche, consisting of a microporous implant in the subcutaneous space, that supports tissue formation whose immune composition is consistent with that within vital organs. Herein, we investigated dynamic gene expression within this immunological niche to provide biomarkers of response to anti-PD-1. In a 4T1 model of metastatic TNBC, we observed sensitivity and resistance to anti-PD-1 based on primary tumor growth and survival. The niche was biopsied before, during, and after anti-PD-1 therapy, and analyzed for cell types and gene expression indicative of treatment refractivity. Myeloid cell-to-lymphocyte ratios were altered between ICB-sensitivity and resistance. Longitudinal analysis of gene expression implicated dynamic myeloid cell function that stratified sensitivity from resistance. A niche-derived gene signature predicted sensitivity or resistance prior to therapy. Analysis of the niche to monitor immunotherapy response presents a new opportunity to personalize care and investigate mechanisms underlying treatment resistance.

Summary: A remote implant identified biomarkers that predict anti-PD-1 response before therapy, providing a unique tool to understand heterologous immunotherapy resistance in triple negative breast cancer.

HER2 and hormone receptors are biomarkers for selecting breast cancer therapy and predicting outcomes. In the era of antibody-drug conjugates (ADC), a relatively low HER2 expression level is adequate for targeting tumor cells. We explored the potential of RNA profiling, determined by next generation sequencing (NGS), to provide more flexible clinical biomarkers as compared with immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). Data from 57 breast cancers was used to study biomarker levels as detected by routine clinical transcriptomic tests. HER2 (ERBB2), estrogen receptor alpha (ESR1), and androgen receptor (AR) mRNA levels were compared with IHC and FISH results. There was a significant overlap in the levels of ERBB2 mRNA between cases scored by IHC as zero, 1+, and 2+. This variation correlated with progression-free survival (PFS). Similarly, the ESR1 RNA accurately reflected estrogen receptor (ER) status. Patients with high AR mRNA had better PFS (p = 0.05). Patients expressing high ER and AR levels had better PFS than those expressing low ESR1 and AR (p = 0.03). These findings suggest that RNA analysis can be an alternative to IHC and FISH and provides continuous data that can better determine cut-off points for predicting response to ADC.

In addition to its universally known role in transferring genetic material, DNA nucleotides and nucleosides are regarded as the most ancient form of extracellular signaling molecules. This unique signaling pathway was first reported by Dr. Albert Szent-Györgyi in 1937 and established by Dr. Geoffrey Burnstock in 1972, who coined the term “purinergic signaling.” The significance of purinergic signaling is now recognized in various cellular processes, including immune responses. With an increased understanding of how changes in immunity impact cancer progression, the groundbreaking successes of immunotherapies, and emerging challenges facing patients receiving these treatments, in this review we revisit the history of purinergic signaling, provide a comprehensive summary of its impact on immune cells, and discuss the therapeutic potential of targeting this pathway for cancer treatment.

Nasopharyngeal cancer (NPC) is common in Saudi Arabia; Most cases are related to the Epstein-Barr virus (EBV), which is associated with treatment failure and a high recurrence rate. Programmed cell death protein 1 (PD-1) and Programmed death-ligand 1 (PD-L1) inhibitors emerged as breakthroughs in cancer treatment, including head and neck cancers. The benefit of these therapies was seen in patients with high expression of PD-L1, which is unknown in our population.  We aim to assess PD-L1 expression in EBV-related NPC patients presented to King Fahd Medical City (KFMC). We identified 41 cases of EBV-related NPC diagnosed between 2016 and 2019. PD-L1 expression was assessed using the Tumor Proportion Score (TPS) and Combined Positive Scores (CPS). Results showed that PD-L1 expression was negative in 51% and 29% using TPS and CPS scores, respectively. High expression of PD-L1, more than 50%, was seen in 17% using TPS and 22% using CPS. There was no statistically significant correlation between the degree of PD-L1 expression by TPS or CPS and many variables, including gender, comorbidities, BMI, TNM staging, and smoking status. Over a median follow-up of 29.7 months, Kaplan-Meier survival curves did not show a statistically significant difference between all groups of PD-L1 expression for O.S. or PFS; However, there were shorter O.S noted with CPS 1%–9%, log-rank p-value = 0.031. These findings support investigating the role of Immunotherapy, especially in the high expression subgroup. Data for these patients' outcomes and further studies to explore the role of PD-L1 in NPC are needed.

Immune checkpoint inhibitors (ICIs) have improved the clinical management of some cancer cases, yet patients still fail to respond to immunotherapy. Dysregulated metabolism is a common feature of many cancers, and metabolites are known to modulate functions in cancer cells. To identify potential metabolic pathways involved in anti-tumor immune response, we employed a metabolic inhibitor-based drug screen in human lung cancer cell lines and examined expression changes in a panel of immune regulator genes. Notably, pharmacologic inhibition of dihydrofolate reductase (DHFR) downregulated cancer cell expression of cluster of differentiation 24 (CD24), an anti-phagocytic surface protein. Genetic modulation of DHFR resulted in decreased CD24 expression, whereas tetrahydrofolate, the product of DHFR, enhanced CD24 expression. DHFR inhibition and the consequent CD24 decrease enhanced T cell-mediated tumor cell killing, whereas replenishment of DHFR or CD24 partially mitigated the immune-mediated tumor cell killing that resulted from methotrexate treatment in cancer cells. Moreover, publicly available clinical data analyses further revealed the link between DHFR, CD24, and the antitumor immune response in lung cancer patients. Our study highlights a novel connection between folate metabolism and the anti-tumor immune response and partially interprets how DHFR inhibitors lead to clinical benefits when combined with cancer immunotherapy agents.

Chimeric antigen receptors (CAR) T-cell therapy is one of the most effective treatments in curing hematologic malignancies. Besides the four CD19 CAR T-cells therapy recently approved by the US Food and Drug Administration (FDA), CD20 CAR T-cell therapy is now another effective treatment option for relapsed or refractory non-Hodgkin lymphoma (NHL). CD20 CAR T-cell infusion has achieved remarkable clinical outcomes in patients with B-cell malignancies. This review will cover the current situations, advantages, limitations, prospects, and application of CD20 CAR T-cell therapy.

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of relapsed/refractory (R/R) B-cell derived hematological malignancies, including acute lymphoblastic leukemia (ALL), B-cell non-Hodgkin lymphoma (B-NHL), and multiple myeloma (MM). CD19-targeted CAR-T cells yield complete remission (CR) rates of about 90% in R/R ALL and about 50% in R/R NHL, respectively, while BCMA-targeted CAR-T cells yield CR rate of about 50%−80% in R/R MM. Notably, the US Food and Drug Administration have approved six CAR-T cell products (tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel, and ciltacabtagene autoleucel) for the treatment of R/R B-NHL, R/R ALL, and R/R MM. However, some patients might not respond to such therapy or quickly relapse after CAR-T cell infusion, which is likely due to the dysfunction and poor persistence of CAR-T cells or the modulation of specific antigen. Thus, alternative treatment strategies must be investigated. In addition, accumulating research have been conducted to discover novel target of antigens with therapeutic efficacy and utility for generating CAR-T cells against acute myeloid leukemia (AML). Safety during CAR-T cell treatment is another important issue, concerning complications such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), pancytopenia, and infection. Despite the fact that the majority of those adverse effects are minimal, the risk of a life-threatening situation still exists. Cautious treatment for severe adverse events requires a multidisciplinary approach with involvement of not only oncologists but also other internal medicine doctors to guarantee diagnosis and treatment in time. Therefore, it is of vital importance to understand the novel advances of CAR-T cell therapy.

This special issue of ImmunoMedicine focuses on novel developments of CAR-T cell therapy for hematological malignancies. The review from Xiangmin Wang (https://doi.org/10.1002/imed.1030) summarized the non-BCMA targeted CAR-T cell therapies for MM. Novel targets including CS1, CD38, CD138, NKG2D, CD70, TACI, and etc. might have the potential to prevent the recurrence and enhance treatment efficiency. The review from Elaine Tan Su Yin (https://doi.org/10.1002/imed.1039) summarized the current breakthrough and future perspectives of CD20-targeted CAR-T cell therapy for hematologic malignancies, especially for R/R B-NHL. The review from Yue Huang (https://doi.org/10.1002/imed.1031) summarized the current achievement and potential AML-associated cell markers of CAR-T cell therapy in AML preclinical studies and clinical trials, and discusses the future directions of CAR-T cell therapy in patients with AML. The review from Yuanyuan Hao (https://doi.org/10.1002/imed.1029) summarized the effects of tumor-derived exosomes (TEXs) on the survival and functions of T cell subsets, as well as their clinical

In recent years, CD19-directed chimeric antigen receptor (CAR) T cell therapy has exhibited significant potency for treating pediatric relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Nonetheless, many patients with disease progressing rapidly may not benefit from this therapy. Actually, 10%–20% of these patients with rapidly progressive disease failed in CAR T cell manufacturing. Besides, some patients died of disease progression earlier than CAR T cells expanding in vivo. How to deal with the fast progressive disease and ensure successful manufacturing and expansion of CAR T cells are still very important questions for the clinicians. In this brief report, some clinical experience to handle these tough situations in our center will be introduced. Bridging chemotherapy and post-CAR antitumor managements help to control progressive blasts and contribute to the success of CAR T cell therapy. The optimal timing of apheresis and adjusted protocol for manufacturing CAR T cells are critical for advanced patients. Optimal treatment options and how they should be applied to advanced B-ALL with heavy disease burden still need to be discussed.

Increasing use of chimeric antigen receptor-T (CAR-T) cell therapy has significantly improved the survival of hematologic malignancy patients, but CAR-T cell treatment is also associated with increased risk of infection. Hence, understanding the characteristics of infection may improve disease prognosis. The data of post-CAR-T therapy infections were obtained from the VigiBase database. We identified a total of 554 infection reports (1001 infection events) involving CAR-T therapy among the 3007 case reports. Infections occurred in 18.42% of cases reported in VigiBase with CAR-T therapy and were most frequently occurred during the first month. Among cases reported in VigiBase, most of the infections were controllable, and only 4.4% of the cases were fatal. Bacteria (60.7%) and respiratory tract infection (50.9%) were the most common infection types. Compared with axicabtagene ciloleucel, infection in patients receiving tisagenlecleucel-T therapy had a higher infection risk (ROR = 1.76; 95% CI = 1.46–2.12, p < 0.001). Meanwhile, fungus infection and mixed infection had poorer prognoses than virus infection. Concerning the disease prognoses, fungal and mixed infection should be given more attention, and extensive prospective studies are much needed to verify these findings.

Immune checkpoint molecules are critical targets of cancer therapies due to their ability to modulate immune responses to cancer. Vasoactive intestinal peptide (VIP) has been proposed as an immune checkpoint molecule, but its predictive and prognostic values have not been established. We evaluated expression levels of VIP and programmed death-ligand 1 (PD-L1) across different cancer types and identified specific cancer histologies in which the expression of these markers is elevated. We conducted systematic analyses of the prognostic and predictive values of VIP and PD-L1 in various cancers using publicly available patient databases and analysis tools including the Gene Expression Profiling Interactive Analysis, PrognoScan, Protein Atlas, cBioportal, and Timer2.0. We also assessed the relationship of PD-L1 and VIP expression levels with survival and the frequencies of tumor-infiltrating immune cells in various cancers. We observed a negative correlation between PD-L1 and VIP expression across cancer types, suggesting the functional redundancy of VIP and PD-L1 immunosuppressive pathways as mechanisms of immune escape. High expression levels of VIP and the association of VIP expression with immune cell infiltrates in the pancreatic adenocarcinoma tumor microenvironment suggest that VIP may be a predictive biomarker for treating pancreatic adenocarcinoma patients with drugs that inhibit the VIP signaling pathway.