Explore the vast range of titles available.

The role of the long noncoding RNA CCAT1 NC_000008.10:g.128220661C > T (rs67085638) in the development of colon cancer has been reported. Therefore, we assessed the prevalence of rs67085638 in patients with gastric cancer (GC). We also evaluated the effect of rs67085638 on B-cell-specific Moloney leukaemia virus insertion site 1 (BMI1) transcripts in primary GC and counterpart histopathologically confirmed disease-free margin tissue. Using high-resolution melting analysis, we evaluated rs67085638 frequency in patients with the GC genotype (n = 214) and controls (n = 502) in a Polish Caucasian population. qRT-PCR was used to determine BMI1 transcripts. We observed the trend of rs67085638 association in all patients with GC ( p trend  = 0.028), a strong risk of the GC genotype in male ( p trend  = 0.035) but not female ( p trend  = 0.747) patients, and the association with non-cardia GC ( p trend  = 0.041), tumour stages T3 ( p trend  = 0.014) and T4 ( p trend  = 0.032), differentiation grading G3 ( p trend  = 0.009), lymph node metastasis stage N3 ( p trend  = 0.0005) and metastasis stage M0 ( p trend  = 0.027). We found that significantly increased BMI1 transcripts were associated with the primary GC genotype classified as grade G3 ( p  = 0.011) and as lymph node metastasis N3 ( p  = 0.010) and counterpart marginal tissues ( p  = 0.026, p  = 0.040, respectively) from carriers of the T/T versus C/C genotypes. rs67085638 may contribute to increased BMI1 transcripts and the progression and rapid growth of GC.

Ovarian cancer comprises a highly complex ecosystem of malignant cells and their surrounding tumor microenvironment (TME), where intricate interactions shape therapeutic responses. Most current predictive models fail to capture the full extent of these interactions. Here, we performed a comprehensive multi-omic analysis of pre-treatment ovarian tumor tissues, integrating clinical, genomic, transcriptomic, and immune features to correlate with pathological therapy response. Our results show that integrating genetic and immune parameters—particularly the interplay between NK cells and TP53 status in high grade serous ovarian cancer (HGSOC), and diverse genetic alterations in non-HGSOC—markedly improves therapy response prediction. We demonstrate that tumor TP53 status governs the persistence of early NK cells in HGSOC, and this persistent NK phenotype is associated with favorable clinical outcomes. Machine learning models harnessing these multi-omic features significantly outperform those based on any single information type alone. These findings highlight the central role of the baseline tumor ecosystem and support a precision oncology framework leveraging integrated multi-omic profiling and advanced analytics to improve prediction and guide treatment strategies. Highlights • Clinical features are insufficient predictors of therapy response. • Genetic and immune features are linked to therapy response. • Early NK cells exhibit a persistent phenotype associated with favorable clinical outcomes. • Machine learning models integrating genomic and immune features significantly improve therapy response prediction. • In HGSOC, therapy response depends on NK cell—TP53 interplay, while in non-HGSOC, it is driven by diverse genetic mutations. • Tumor TP53 status regulates persistence of NK cells in HGSOC.

A recently paper published in Cell reports that dendritic cells （DCs） are dysfunctional in the tumor environment. Tumor impairs DC function through induction of endoplasmic reticulum stress response and subsequent disruption of lipid metabolic homeostasis.

Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c + cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c + cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c + cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies. Myeloid cell subsets are playing important roles in antitumour immunity, and genes affecting their functions are potential targets for immunotherapy. Here authors show that genomic deletion of Pikfyve in CD11c + cells results in tumour growth inhibition via enhanced antigen presentation and priming of antigen-specific CD8 + T cells in a mouse tumor model.

In mouse models of cancer, the inhibition of a set of regulatory proteins improves checkpoint-blockade therapy by causing regulatory T cells to produce the cytokine interferon-γ.

Immune phenomena during the preimplantation period of pregnancy are poorly understood. The aim of our study was to assess the capacity for antigen presentation of splenic antigen-presenting cells (APCs) derived from pregnant and pseudopregnant mice in in vitro conditions. Therefore, sorted CD11c+ dendritic cells and macrophages F4/80+ and CD11b+ presenting ovalbumin (OVA) were cocultured with CD4+ T cells derived from OT-II mice’s (C57BL6/J-Tg(TcraTcrb)1100Mjb/J) spleen. After 132 hours of cell culture, proliferation of lymphocytes (ELISA-BrdU), activation of these cells (flow cytometry), cytokine profile (ELISA), and influence of costimulatory molecules blocking on these parameters were measured. We did not detect any differences in regulation of Th1/Th2 cytokine balance. CD86 seems to be the main costimulatory molecule involved in the proliferation response but CD80 is the main costimulatory molecule influencing cytokine secretion in pregnant mice. In conclusion, this study showed that CD80 and CD86 costimulatory molecules regulate OT-II CD4+ T lymphocyte proliferation and cytokine response in cocultures with antigen-presenting cells derived from pregnant and pseudopregnant mice. The implications of these changes still remain unclear.

The tumor microenvironment represents a stressful cellular environment. Zou and colleagues show that T reg cells in tumors have heightened sensitivity to apoptosis, but unexpectedly this increases their suppressive potency. Live regulatory T cells (T reg cells) suppress antitumor immunity, but how T reg cells behave in the metabolically abnormal tumor microenvironment remains unknown. Here we show that tumor T reg cells undergo apoptosis, and such apoptotic T reg cells abolish spontaneous and PD-L1-blockade-mediated antitumor T cell immunity. Biochemical and functional analyses show that adenosine, but not typical suppressive factors such as PD-L1, CTLA-4, TGF-β, IL-35, and IL-10, contributes to apoptotic T reg -cell-mediated immunosuppression. Mechanistically, apoptotic T reg cells release and convert a large amount of ATP to adenosine via CD39 and CD73, and mediate immunosuppression via the adenosine and A 2A pathways. Apoptosis in T reg cells is attributed to their weak NRF2-associated antioxidant system and high vulnerability to free oxygen species in the tumor microenvironment. Thus, the data support a model wherein tumor T reg cells sustain and amplify their suppressor capacity through inadvertent death via oxidative stress. This work highlights the oxidative pathway as a metabolic checkpoint that controls T reg cell behavior and affects the efficacy of therapeutics targeting cancer checkpoints.

Glucose availability is limiting in tumor environments. Zou and colleagues show that reduced glycolytic metabolism in T cells within tumors suppresses expression of the methyltransferase EZH2, which limits production of antitumor effector molecules and enhances T cell apoptosis. Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA–mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2 + CD8 + T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.

Immunoregulatory activity of type I interferons (IFNs) and estrogen is convergent in some cases of autoimmune disorders. The aim of our study was to determine whether a potent interaction of IFN and estradiol (E2) has an influence on immune response and estrogen receptor alpha (ER-α) expression in antigen-presenting cells in a model of experimental autoimmune orchitis (EAO). C3H/He/W male mice were immunized with testicular germ cells (TGCs) and orally treated with interferon tau (IFN-τ), E2, or both simultaneously. The delayed-type hypersensitivity reaction was intensified after the administration of either IFN-τ or E2, but their co-administration had no effect. IFN-τ treatment increased immunoglobulin G2a (IgG2a) and decreased IgG1 levels of TGC-specific antibodies, whereas E2 abolished the effects of the used cytokine. The total splenic cellularity and the number of spleen CD11c+MHC II+ and F4/80+MHC II− cells were increased after IFN-τ treatment, whereas E2 antagonized this effect. After IFN-τ administration the level of ER-α was significantly higher in F4/80+MHC II− cells, whereas E2 had no effect. However, the administration of E2 significantly reduced the ER-α level in F4/80+MHC II+ and CD11c+MHC II+ cells in comparison with the IFN-τ–treated groups. In the EAO model, the type I IFN and E2 cooperated at the general and cellular levels of immune response, but E2 treatment usually abolished the effects exerted by the cytokine.

SummaryESK981 is a potent tyrosine kinase and PIKfyve lipid kinase inhibitor. This phase II trial evaluated the efficacy of ESK981 as a single agent in patients with androgen receptor-positive (AR +) metastatic castration-resistant prostate cancer (mCRPC). Eligible patients had mCRPC with progression on AR-targeted agents and without prior chemotherapy treatment. Each patient received 160 mg ESK981 once daily for 5 days per week for 4 weeks per cycle (except for an adverse event (AE) occurrence). The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included the time and the duration of PSA response, PSA progression rates, PSA progression free survival (PFS) and overall survival (OS). Exploratory investigations included whole exome sequencing in patients before treatment, and morphological evaluation of biopsy samples pre- and post-treatment. PSA was evaluated in 13 patients. Only one patient (7.7% two-sided 95% Wilson CI (0.4%, 33.3%)) experienced a reduction in their PSA levels by 50% or more. The most common grade 3 treatment-related AEs were cardiac disorders, diarrhea, hypertension, alanine transaminase and aspartate transaminase elevations. No grade 4–5 events occurred. Median PFS was 1.8 months, and median OS was 12.1 months. Peripheral immune cells showed increased T cell activation and cytokine production in two patients who received 12-weeks of ESK981. Although relatively well tolerated, ESK981 alone showed no anti-tumor activity in patients with AR + mCRPC and its further evaluation as a single agent in AR + mCRPC is not warranted. (Trial registration: ClinicalTrials.gov, NCT03456804. Registration date: March 7, 2018).