Nature cancer最新文献

Multiple myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We developed an Immune Atlas of MM by generating profiles of 1,397,272 single cells from the bone marrow (BM) of 337 newly diagnosed participants and characterized immune and hematopoietic cell populations. Cytogenetic risk-based analysis revealed heterogeneous associations with T cells of BM, with 17p13 deletion showing distinct enrichment of a type 1 interferon signature. The disease progression-based analysis revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing participants. Furthermore, signaling analyses suggested active intercellular communication involving a proliferation-inducing ligand and B cell maturation antigen, potentially promoting tumor growth and survival. Lastly, using independent discovery and validation cohorts, we demonstrated that integrating immune cell signatures with known tumor cytogenetics and individual characteristics significantly improves stratification for the prediction of survival.

In the SCORES study ( NCT04908787 ), women with ovarian cancer that progressed within 6 months after completing platinum-based therapy were randomized (2:1) to receive suvemcitug (1.5 mg kg^-1), an antibody to vascular endothelial growth factor or placebo every 2 weeks, with chemotherapy (paclitaxel, topotecan or PEGylated liposomal doxorubicin). The primary endpoint was progression-free survival (PFS). The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, disease control rate, duration of response, quality of life, safety, pharmacokinetics and antidrug antibodies. Between June 5, 2021 and October 11, 2024, 421 participants were randomized (49.4% and 49.4% previously exposed to antiangiogenic agents and poly(ADP-ribose) polymerase inhibitors, respectively). Median PFS was 5.5 and 2.7 months in the suvemcitug and placebo arms, respectively (hazard ratio: 0.46, 95% confidence interval (CI): 0.35-0.60, P < 0.001), meeting the primary endpoint. Median OS was 15.3 versus 14.0 months, respectively (hazard ratio: 0.77, 95% CI: 0.60-0.99, P = 0.03). Decreased neutrophil count and decreased white blood cell count were the most common grade ≥3 treatment-emergent adverse events (TEAEs) in the suvemcitug arm. No suvemcitug-related grade 5 TEAE occurred. In conclusion, the addition of suvemcitug to chemotherapy significantly improved PFS and OS, with tolerable toxicities.

Cancer immunotherapies have revolutionized cancer treatment, yet many patients fail to respond. Activating innate immunity offers a promising approach to enhance therapeutic efficacy, but the signaling kinases directly regulating this process to boost antitumor responses remain elusive. Here we conduct an in vivo kinome CRISPR screen and identify CDK10 as a key suppressor of tumor immune surveillance. Mechanistically, CDK10 phosphorylates DNMT1 and RAP80 to reduce the accumulation of double-stranded RNA and R-loops, which alleviates the activation of innate immune pathways mediated by MDA5 and cGAS. Kinase inhibitor screens identify NVP-AST487 and ponatinib as selective CDK10 inhibitors. Both genetic and pharmacological inhibition of CDK10 activates MDA5 and cGAS pathways, fostering an immunoactive tumor microenvironment that enhances cancer immunotherapy in multiple mouse tumor models. Clinically, low CDK10 expression in tumors correlates with better immunotherapy responses. These findings establish CDK10 as a pivotal modulator of tumor immunity and a potential therapeutic target.

As part of canonical Wnt signaling, T cell factor (TCF)-β-catenin complexes promote MYC-dependent proliferation. Lesions of the β-catenin protein degradation machinery are common oncogenic drivers. Here, we show that B cell acute lymphoblastic leukemia (B-ALL) lacks these mutations and critically depends on unencumbered β-catenin protein degradation. Compared to solid tumors, we found that mouse and human B-ALL express β-catenin protein at much lower levels; β-catenin protein was constitutively phosphorylated by glycogen synthase kinase 3B (GSK3β) and poised for proteasomal degradation. Instead of TCF-β-catenin complexes to activate MYC, β-catenin paired with B lymphoid Ikaros and NuRD complex factors, resulting in MYC repression and acute cell death. To leverage β-catenin protein degradation as a previously unrecognized vulnerability in B-ALL, we validated GSK3β inhibition in patient-derived xenograft models in vivo. CRISPR screens confirmed β-catenin protein degradation as a central mechanistic target of established GSK3β inhibitors. As several GSK3β inhibitors achieved favorable safety profiles in clinical trials, our results provide a rationale for repurposing these compounds for persons with refractory B cell malignancies.

Individuals with non-small-cell lung cancer (NSCLC) with metastases to the ipsilateral mediastinum or subcarinal lymph nodes (N2 disease) have poor long-term survival. This exploratory analysis from the randomized phase 3 CheckMate 77T study assessed clinical outcomes by nodal status in individuals with stage III NSCLC who received neoadjuvant nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab (nivolumab) versus neoadjuvant chemotherapy followed by surgery and adjuvant placebo (placebo). Here we show that among patients with N2 disease, nivolumab versus placebo improved event-free survival (1-year rate, 70% versus 45%; hazard ratio, 0.46 (95% confidence interval, 0.30-0.70)) and pathological complete response rate (22.0% versus 5.6%); 77% versus 73% had definitive surgery, of whom 84% versus 74% received a simple lobectomy. Furthermore, nivolumab improved outcomes versus placebo in patients with multistation N2 NSCLC (1-year event-free survival rate: 71% versus 46%; hazard ratio, 0.43 (0.21-0.88); pathological complete response rate, 29.0% versus 2.7%). In the N2 subgroup with definitive surgery, 67% and 59% of patients had nodal downstaging after surgery (57% versus 44% downstaged to node-negative disease). Median EFS in randomized patients with stage III non-N2 NSCLC was not reached with nivolumab and 17.0 months with placebo (1-year EFS rate, 74% versus 62%; hazard ratio, 0.60 (0.33-1.08)). No new safety signals were identified. These findings support perioperative nivolumab plus neoadjuvant chemotherapy as an efficacious treatment for stage III N2 disease and suggest that N2 status may not predict poor prognosis in resectable NSCLC treated with perioperative immunotherapy. ClinicalTrials.gov identifier: NCT04025879 .

Plasticity is a hallmark of aggressive tumors, including glioblastoma (GBM), enabling tumor cells and the tumor microenvironment (TME) to adapt to diverse niches and evade treatment. Here, we discuss how innate and adaptive immune players cooperate in time and space to create an immunosuppressive TME that supports GBM growth and confers resistance to conventional treatments and immunotherapies. We highlight how therapeutic interventions reshape the TME, underscoring the need for targeted approaches to overcome resistance. We introduce the concepts of local TME priming and TME rewiring as necessary foundations for achieving more effective and durable clinical responses in the future.

Insufficient functional T cell persistence impedes therapeutic success of chimeric antigen receptor (CAR) therapies. Here we performed a CAR-adapted base-editing screen of PIK3CD, a key regulator of T cell function, metabolism and fate. We identified point mutations that beneficially modulate CAR T cell profiles in 4-1BBz and 28z CAR T cells, respectively. We found that point mutations with differing effects on phosphatidylinositol-3-kinase delta (PI3Kδ) signaling activity were advantageous in distinct CAR contexts: The PI3Kδ-activating substitution E81K enhanced proliferation, metabolic fitness and effector function of 4-1BBz CARs, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo. Conversely, the PI3Kδ-attenuating substitution L32P improved T cell memory formation and functionality of 28z CAR T cells. Together, our approach of rational optimization of activation-dependent signaling through targeted allelic reprogramming (ROADSTAR) illustrates the importance of CAR design-specific fine-tuning of intrinsic T cell signaling and demonstrates the potential of base editing for next-generation cellular therapies.

CD19-negative relapse occurs in ~30% of persons with relapsed or refractory large B cell lymphoma (LBCL) who respond to axicabtagene ciloleucel (axi-cel; CD19-directed chimeric antigen receptor (CAR) T cell therapy). In this phase 2 single-arm study, 26 participants with chemorefractory LBCL received axi-cel in combination with rituximab. The primary endpoint was investigator-assessed complete response rate; select secondary endpoints included duration of response (DOR), axi-cel pharmacokinetics and safety. The complete response rate was 73%. Median DOR was 26.0 months; 46% of participants had an ongoing response at data cutoff. Peak CAR T cell (normalized by tumor burden) and rituximab area-under-the-curve levels were elevated in participants with complete or ongoing response. Axi-cel plus rituximab treatment led to durable responses with no new safety signals despite persistent B cell aplasia and pharmacokinetics of axi-cel were unaffected, indicating that dual targeting of CD19 and CD20 is a feasible and safe approach to potentially limit antigen escape. ClinicalTrials.gov registration: NCT04002401 .