Cancer research communications最新文献

To increase the achievement of negative R0 surgical margins and increase the low survival rates of pancreatic cancer, improvements in assessing tumor margins during surgical resections are needed. This can be accomplished by using pancreatic cancer-targeted fluorescence molecular imaging agents to intraoperatively detect tumor margins in real time. Because Toll-like receptor 2 (TLR2) is broadly expressed among many cancer types including pancreatic adenocarcinomas, a high-affinity TLR2-targeted fluorescence molecular imaging agent (TLR2L-800) was developed. We investigate the potential for increased survival by employing real-time intraoperative tumor detection in a preclinical orthotopic human pancreatic xenograft tumor model using TLR2L-800. Three cohorts of nude mice bearing orthotopic human pancreatic xenograft tumors were intravenously injected with TLR2L-800. At 24 hours postinjection, one cohort underwent in vivo fluorescence-guided surgical removal of tumors using a real-time fluorescence imaging platform, a second cohort underwent visible light surgery (VLS), and a third cohort did not undergo surgery. A fourth, nontumor-bearing cohort was administered TLR2L-800 with no surgery. At 41 days postsurgery, the survival rates were 53% for the fluorescence-guided surgery (FGS) group and 0% for both the VLS and the tumor-bearing no-surgery group. The overall 200-day survival rate of 35% for the FGS group was significant compared with 0% for the VLS group (P value = 0.0018). This study demonstrates the potential of increasing disease-free survival for patients with pancreatic cancer by increasing the attainment of R0 margins using a novel tumor-targeted lipopeptide ligand-based fluorescence molecular imaging agent, TLR2L-800, during real-time FGS.

Significance: Human TLR2 is broadly expressed among pancreatic adenocarcinomas, and the highly specific TLR2L-800 fluorescence molecular imaging agent has potential for use in fluorescence-guided surgery to increase R0 margins and improve patient survival.

CD8+ T cells are crucial for antitumor immunity. In higher-risk myelodysplastic neoplasms (HR-MDS) and acute myeloid leukemia (AML), CD8+ T cells exhibit altered functionality. To address their role in the course of the disease, we performed in-depth immunophenotypic analysis of 104 pre-treatment bone marrow (BM) samples using mass and flow cytometry and observed an increased frequency of the CD57+CXCR3+ subset of CD8+ T cells in patients who failed azacitidine (AZA) therapy. Furthermore, an increased baseline frequency (>29%) of the CD57+CXCR3+CD8+ T cell subset was correlated with poor overall survival. We performed scRNA-seq to assess the transcriptional profile of BM CD8+ T cells from treatment-naive patients. The response to AZA was positively associated with the enrichment of IFN-mediated pathways, whereas an enhanced TGF-β signaling signature was observed in non-responders. Our results suggest that targeting CD8+ T cells with inhibitors of TGF-β signaling in combination with AZA is a potential therapeutic strategy for HR-MDS and AML.

Significance: Here, RNAi library screening reveals that multiple G2/M and kinetochore components, including TTK/monopolar spindle 1, modulate TNFα-induced NF-κB activation, cell survival, and genotoxicity, underscoring their potential importance as therapeutic targets in HNSCC.

Purpose: Real-world, large-scale studies on the association between immune-related adverse events (irAE) and immune checkpoint inhibitor therapy effectiveness are limited. We evaluated overall survival (OS) and progression-free survival based on the occurrence and grade of irAEs.

Patients and methods: We used data from Japanese patients with unresectable advanced or recurrent non-small cell lung cancer (NSCLC) who received atezolizumab and were enrolled in J-TAIL, a multicenter, prospective, single-arm observational study.

Results: Among the 1,002 patients, 190 (19.0%) developed irAEs. The most common irAEs were skin disorders (3.8%) of any grade and interstitial lung disease (1.5%) of grade ≥3. Patients who developed irAEs within 4 or 6 weeks of treatment initiation had higher baseline C-reactive protein levels than those without irAEs. OS was longer in patients with irAEs [HR, 0.66; 95% confidence interval (CI), 0.54-0.82], particularly in those with low-grade irAEs (HR, 0.45; 95% CI, 0.33-0.62), than in patients without irAEs. The HR (95% CI) for OS in patients with low-grade and high-grade skin or endocrine disorder-related irAEs was 0.42 (0.28-0.64) and 0.37 (0.15-0.88), respectively. The HR (95% CI) for OS in patients with low-grade and high-grade irAEs other than skin or endocrine disorders was 0.44 (0.30-0.65) and 1.27 (0.96-1.69), respectively.

Conclusions: In patients with unresectable advanced or recurrent NSCLC treated with atezolizumab in real-world settings, irAEs are associated with a clinical benefit except in those with high-grade irAEs other than skin and endocrine disorders.

Significance: Immune checkpoint inhibitors are useful for treating NSCLC but can cause life-threatening irAEs. This study had a large sample size and stratified the analysis by irAE type and grade. The results suggest that improved management of irAEs may improve the therapeutic effect of atezolizumab.

Significance: Mechanistically guided drug repurposing has been made possible by systematically integrating pharmacologic and CRISPR-Cas9 screen data. Our study discovers the biomarker and cell death mechanisms underpinning sensitivity toward AZD5582, an antagonist of the inhibitor of apoptosis family protein. Our findings have important implications for improving future trial design for patients with OSCC using this emerging drug class.

Homologous Recombination Deficiency (HRD) drives genomic instability in multiple cancer types and renders tumors vulnerable to certain DNA damaging agents such as PARP inhibitors. Thus, HRD is emerging as an attractive biomarker in oncology. A variety of in silico methods are available for predicting HRD; however, few of these methods have been applied to cell lines in a comprehensive manner. Here we utilized two of these methods, "CHORD" and "HRDsum" scores, to predict HRD for 1,332 cancer cell lines and 84 non-cancerous cell lines. Cell lines with biallelic mutations in BRCA1 or BRCA2, which encode key components of the homologous recombination pathway, showed the strongest HRD predictions, validating the two methods in cell lines. A small subset of BRCA1/2-wildtype cell lines were also classified as HRD, several of which showed evidence of epigenetic BRCA1 silencing. Similar to HRD in patient samples, HRD in cell lines was associated with p53 loss, was mutually exclusive with microsatellite instability and occurred most frequently in breast and ovarian cancer types. In addition to validating previously identified associations with HRD, we leveraged cell line-specific datasets to gain new insights into HRD and its relation to various genetic dependency and drug sensitivity profiles. We found that in cell lines, HRD was associated with sensitivity to PARP inhibition in breast cancer, but not at a pan-cancer level. By generating large-scale, pan-cancer datasets on HRD predictions in cell lines, we aim to facilitate efforts to improve our understanding of HRD and its utility as a biomarker.

Cancer progression and response to therapy are inextricably reliant on the co-evolution of a supportive tissue microenvironment. This is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a tumor type characterized by expansive and heterogeneous stroma. Herein, we employed single cell RNAseq and spatial transcriptomics of normal, inflamed, and malignant pancreatic tissues to contextualize stromal dynamics associated with disease and treatment status, identifying temporal and spatial trajectories of fibroblast differentiation. Using analytical tools to infer cellular communication, together with a newly developed assay to annotate genomic alterations in cancer cells, we additionally explored the complex intercellular networks underlying tissue circuitry, highlighting a fibroblast-centric interactome that grows in strength and complexity in the context of malignant transformation. Our study yields new insights on the stromal remodeling events favoring the development of a tumor-supportive microenvironment and provides a powerful resource for the exploration of novel points of therapeutic intervention in PDAC.

Significance: Further investigation of the potential susceptibility regions identified in our study may lead to a better understanding of glioma genetic risk and the underlying biological etiology of glioma. Our study suggests sex may play a role in genetic susceptibility and highlights the importance of sex-specific analysis in future glioma research.

Significance: Mathematical modeling yields general principles for optimization of TRT in mouse models of multiple myeloma that can be extrapolated to other cancer models and clinical settings.

While immune checkpoint blockade (ICB) therapy has shown promising results in a small subset of colorectal cancer patients with high microsatellite instability (MSI-H), the majority of patients with colorectal cancer do not respond to ICB therapy. The main obstacle to the success of immunotherapy in cancer treatment is the exhaustion of tumor-infiltrating lymphocytes (TILs). Elucidating the spatial organization of immune checkpoints within the tumor microenvironment could pave the way for the development of novel prognostic tools and therapeutic strategies to enhance antitumor immune responses. To clarify the spatial and functional diversity of tumor-infiltrating lymphocytes (TILs) in the colorectal tumor microenvironment (TME), we performed multiplexed IHC to examine the exhaustion of TILs in the TME (the expression of PD-1 and TIM-3 (T-cell immunoglobulin and mucin-domain-containing protein 3), which are major biomarkers of T-cell exhaustion) and Lasso-Cox analyses of the correlation between CRC prognosis and TME features. For proof of concept, the antitumor efficacy of TIM-3 and PD-1 dual blockade in CRC was further evaluated in a CT26 subcutaneous tumor model of human CRC. We found that the spatial context of PD-1 and TIM-3 successfully predicted the overall survival of CRC patients independent of TNM stage. Dual targeting of PD-1 and TIM-3 in mouse tumor models inhibited tumor progression and reduced T-cell exhaustion, indicating a potential strategy for improving the clinical treatment of CRC.