"Tumor-associated macrophages" (TAMs) form a significant cell population in malignant tumors and contribute to tumor growth, metastasis, and neovascularization. Gliomas are characterized by extensive neo-angiogenesis, and knowledge of the role of TAMs in neovascularization is important for future anti-angiogenic therapies. The phenotypes and functions of TAMs are heterogeneous and more complex than a classification into M1 and M2 inflammation response types would suggest. In this review, we provide an update on the current knowledge of the ontogeny of TAMs, focusing on diffuse gliomas. The role of TAMs in the regulation of the different processes in tumor angiogenesis is highlighted and the most recently discovered mechanisms by which TAMs mediate resistance against current antivascular therapies are mentioned. Novel compounds tested in clinical trials are discussed and brought in relation to different TAM-related angiogenesis pathways. In addition, potential therapeutic targets used to intervene in TAM-regulated tumor angiogenesis are summarized.
Abstract Background: Combing anti-PD-(L)1 antibody with chemotherapy in neoadjuvant therapy of gastric/gastroesophageal junction (G/GEJ) adenocarcinomas is a promising strategy, but clinical data are remain insufficient. Whether immunotherapy biomarkers in previous studies (TMB, MSI, PD-L1, etc.) have equivalent predictive value for G/GEJ remains to be verified. In this phase II clinical trial of tislelizumab in combination with chemotherapy, potential therapy-related biomarkers in tumor samples, and changes in the tumor microenvironment during treatment were analyzed, and a predictive model for efficacy was developed. Methods: This was a prospective, single-center, single-arm, phase II trial. Patients with G/GEJ adenocarcinomas (stage cT3-4aN+M0) were treated with PD-1 inhibitor tislelizumab in combination with oxaliplatin plus capecitabine (XELOX) as neoadjuvant treatment for 2 or 3 cycles. The primary endpoint was the major pathological response (MPR). The secondary endpoints included pathological complete response (pCR) rate, R0 resection rate, and safety. Tumor samples underwent RNA-sequencing (Amoy Diagnostics Co Ltd, Xiamen, China), to identify potential biomarkers, and a predictive model was developed to explore factors influencing tumor response and survival. Results: 28 patients were enrolled; mean age was 59.5 years (SD = 8.2), 19 (67.9%) patients were male; 14 (50.0%) patients with primary tumor location in the stomach, and 14 (50.0%) patients with primary tumor location in the GEJ. All patients were EB virus negative. Except one patient with PMS2 loss, 27 patients were pMMR. Nine (32.1%) patients achieved MPR after treatment, with four (14.3%) of them achieved pCR. The R0 resection rate was 96.4%, with 14 (50.0%) patients achieved objective response. No serious adverse events were reported. The most common grade 2 TRAEs during neoadjuvant treatment were anemia (5 of 28, 17.86%) and nausea (3 of 28, 10.71%). Analysis of differentially expressed genes revealed enrichment of the antigen processing and presentation pathway in the MPR group, while the TGF-β signaling pathway was enriched in the non-MPR group. Notably, the differential immune microenvironment analysis also uncovered significant differences in the TGF-β signature between the MPR and non-MPR groups. Additionally, a therapeutic response prediction model (HT score) was developed with an AUC of 0.98 (0.932-1) in the training set, and its performance was validated in publicly available datasets. Conclusion: Tislelizumab combined with XELOX holds promise as a neoadjuvant therapy for resectable G/GEJ adenocarcinomas, especially for EBV- and pMMR population, offering a well-tolerated safety profile. Moreover, the HT score has the potential to predict treatment efficacy in this regimen. Trial registration numbers: NCT05507658 and NCT05508399. Citation Format: Haikun Zhou, Tao Han, Lei Tuo, Qingchuan Yang, Ruiqi Gao, Pengfei Yu, Jiangpeng Wei, Changbin Zhu, Jin Wang, Peng Cheng, Xiang Kang, Sihui Pi, Hui Liu, Xiaoxi Pan, Xiaohua Li, Gang Ji. Tislelizumab combined with XELOX as a neoadjuvant therapy for locally advanced gastric and gastroesophageal junction adenocarcinomas: A prospective, phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6400.
e21024 Background: Alterations of TP53, EGFR, KRAS genes are of importance in LUAD etiology, vital prognostic markers as well as therapeutic targets as recently reported. In addition, in advanced or metastatic NSCLC, concomitant mutations of TP53 with EGFR or KRAS closely associated with prognosis and TKIs’ efficacy. While, distribution of concomitant mutations of TP53, EGFR and KRAS in early stage or resectable LUAD remained to be elucidated. Methods: 434 patients with defined pathological diagnosis of LUAD were recruited from 1 st .Jan.2019-31 st .Dec.2019, which made 468 FFPE blocks for the study. Histology and composition were given by authorized by pathologist. Genomic DNA from FFPE samples and peripheral blood was extracted. 636 cancer-related genes were specifically captured and sequenced by MGI-seq 2000. Association of concomitant status with clinical and genomic characteristics was further analyzed. Results: Generally, TP53, EGFR and KRAS mutation rate is 26.7%, 60.9% and 10% respectively. Among these samples, Subtypes of EGFR mutations significantly differed in between tumors rising in left and right lung (P = 0.048). Tumors with KRAS mutations occurred more easily in right lung than those with TP53 or EGFR mutations (P = 0.012, P = 0.043 respectively). In addition, histology subtype and clinical stage were closely associated with TP53, EGFR and KRAS mutation status (P < 0.001). 90 samples (19.2%) carried concomitant TP53 and EGFR mutation, 14 samples (3%) were TP53/KRAS co-mutated. LUAD samples with EGFR amplification had higher rate of concomitant TP53/EGFR mutations (RR:1.1,95%CI: 1.032 to 1.159,P = 0.0009). Moreover, KRAS G13 mutated samples more easily co-mutated with TP53 mutations compared with those with mutations in G12 loci (RR:1.33,95%CI: 1.24 to 1.37,P = 0.024). Further, samples with non-concomitant TP53 mutations had highest level of tumor mutation burden (muts/Mb) (median TMB = 9.74 vs 2.05 for TP53/EGFR/KRAS wild type, P < 0.0001). Samples with concomitant TP53/EGFR mutations and TP53/KRAS mutations displayed higher TMB level than their non-concomitant compartment (P < 0.001 and P = 0.05 respectively). Conclusions: TP53,EGFR and KRAS mutations and their concomitant mutation status displayed diverse correlation with spatial, clinical and genomic characteristics in resectable LUAD patients. This correlation may indicate complex biological heterogeneity of LUAD which may need further exploration.
e15534 Background: In colorectal cancer (CRC), the therapeutic potential of immune checkpoint inhibitors (ICIs) is limited to the patients with mismatch repair deficient (dMMR)/high microsatellite instable (MSI-H) tumors, which accounts for less than 5% of CRC patients. While, patients with mismatch repair proficient (pMMR)/microsatellite stable (MSS) tumors represent the vast majority (≈ 95%), particularly those with similar inflammatory tumour microenvironment characteristics to dMMR/MSI-H patients are at risk of losing the opportunity to receive appropriate treatment. Thus, there is an urgent clinical need for biomarkers that can accurately predict prognosis of CRC patients, and assist in selection of patients who may benefit from immunotherapy. Methods: A public database, GEO (GSE39582, n = 502), was used as a training cohort to assess the characteristics associated with immune activation. Individuals with immune characteristics similar to dMMR/MSI-H were identified through GSVA and unsupervised clustering analysis, and defined as MSI-Like. Limma analysis identified MSI-Like immune activation characteristic, and immune activation-related prognostic models were developed by LASSO and COX regression. In addition, the applicability of immunotherapy for immune activation-related prognostic score was estimated in an external validation cohort (n = 96) from an Asian institution. Results: 113 differentially expressed genes between MSI-Like and non-MSI-Like pMMR/MSS samples were defined as immune activation- related characteristics of MSI-Like. After stepwise regression analysis, the characteristics were reduced to 6 key genes, and combined with their regression coefficients to construct a model. Overall survival was significantly shorter in high-risk [Immune Activation-related Risk Score (IARS) ≥ 0] group than in low-risk (IARS < 0) group (p < 0.0001). The area under the ROC curve (AUC) values at 1, 5 and 10 years were 0.683, 0.708 and 0.765, respectively. Furthermore, in multiple CRC data sets, the IARS can screen out the low-risk group with significantly better prognosis (p < 0.05). Additionally, low-risk group showed more expression of immune activation-related genes compared to high-risk group. IARS did not shown significant correlations with clinically characteristic factors (e.g., gender, age, stage, etc.) or gene mutations (including TP53, KRAS and BRAF). Conclusions: For a subset of pMMR/MSS patients with immune activation characteristics similar to those of dMMR/MSI-H patients, an immune activation-related risk score model was constructed based on 6 genes associated with immune activation characteristics. This model can effectively predict the prognosis of patients and also help to assess the adaptability of patients to immunotherapy. These findings have the potential to provide new insights into the immunotherapy of patients with pMMR/MSS CRC.
The majority of glioma-associated microglia/macrophages have been identified as M2-type macrophages with immune suppressive and tumor supportive action. Recently, the extracellular adenosine deaminase protein Cat Eye Syndrome Critical Region Protein 1 (CECR1) was shown to regulate macrophage maturation. In this study, we investigate the role of CECR1 in the regulation of the glioma-associated macrophage response.Expression of CECR1 was assessed in human glioma samples. CECR1-mediated macrophage response was studied in vitro, using donor derived CD14+ monocytes and the THP-1 monocytic cell line. The response of the human glioma cell line U87 to conditioned medium of macrophages preconditioned with recombinant human CECR1 or CECR1 silencing was also assessed.CECR1 was strongly expressed in high-grade gliomas (P < .001) and correlated positively with the M2 phenotype markers in tumor-associated microglia/macrophages (TAMs) (overall, P < .05). In vitro studies confirmed the presence of a significantly higher level of CECR1 expression in M2-like macrophages exposed to U87 conditioned medium (P < .001). CECR1 knockdown or stimulation of macrophages affected differentiation toward the M2-like phenotype. Stimulation of U87 cells with conditioned medium of CECR1 knockdown or stimulated macrophages affected tumor cell proliferation and migration, coinciding with altered intracellular signaling of mitogen-activated protein kinase (MAPK). In glioma tissue samples, CECR1 expression correlated with Ki67 and MAPK signaling protein.CECR1 is a potent regulator of TAM polarization and is consistently highly expressed by M2-type TAMs, particularly in high-grade glioma. Paracrine effects induced by CECR1 in M2-like TAMs activate MAPK signaling and stimulate the proliferation and migration of glioma cells.
e21002 Background: Though targeted, immune-, even combinational therapies have been applied widely, platinum-based chemotherapy still plays irreplaceable role as initial management for patient with either resected or advanced NSCLC without actionable target. Platinum is sought to increase DNA damage burden inducing cell death, especially in cells with intrinsic DNA damage repair (DDR) dysfunction. This study aims to explore impact of DDR genes as well as co-occurrence of TP53 mutations on prognosis of NSCLC patients. Methods: 110 NSCLC patients were consecutively recruited from 2016-2018. 508 cancer related genes were sequenced by BGI-seq 500. COX regression was used to evaluate risk of disease progression as well as cancer-related death among patients with various DDR/TP53 status. Results: 61 NSCLC patients with stage II-IV (median age of onset: 55 years) were recruited who received platinum-based therapy as adjuvant or 1 st line systemic therapy. Till 15 th .Oct.2019, median follow-up time was 24 months. 21 patients (34.4% of 61) carried DDR mutations. TP53 mutations were detected in 36 patients (59% of 61). 11 patients (18% of 61) displayed TP53/DDR co-mutations. COX regression analysis indicated NSCLC patients with DDR mutation would have lower risk of disease progression (HR:0.37, P = 0.19) as well as superior overall survival time (HR:0.35, P = 0.035). Patients with DDR co-mutations had no superior survival benefit. Patients with HRR mutations presented similar result. Patients with TP53 mutations had similar risk as ones with other mutations. While those with DDR concomitant mutations showed significantly improved clinical benefit (HR for PFS:0.28, P = 0.05; HR for OS:0.22, P = 0.023). Conclusions: DNA damage repair genes in Chinese NSCLC patients may play vital roles in predicting efficacy of platinum-based chemotherapy even in the context of TP53 co-mutation. Further, combination of BRCA2 and PALB2 may be better associated with patients’ prognosis. Large cohort should be set up to validate this finding in near future. [Table: see text]
Abstract Not all MET exon 14 skipping ( MET ex14) NSCLC patients benefited from MET inhibitors. We hypothesized an inter-tumoral heterogeneity in MET ex14 NSCLC. Investigations at genomic and transcriptomic level were conducted in MET ex14 NSCLC samples from stage I-III and recurrent/metastatic patients as discovery and validation cohort. Four molecular subtypes were discovered. MET-Driven subtype, with the worst prognosis, displayed MET overexpression, enrichment of MET-related pathways, and higher infiltration of fibroblast and regulatory T cells. Immune-Activated subtype having the most idea long-term survival, had higher tertiary lymphoid structures, spatial co-option of PD-L1 + cancer cells, and GZMK + CD8 + T cell. FGFR- and Bypass-Activated subtypes displayed FGFR2 overexpression and enrichments of multiple oncogenic pathways respectively. In the validation cohort, patients with MET-Driven subtype had better response to MET inhibitors than those with MET overexpression. Thus, molecular subtypes of MET ex14 NSCLC with distinct biological and clinical significance may indicate more precise therapeutic strategies for MET ex14 NSCLC patients.
Abstract Background: FGFR inhibitors are currently in clinical development or approved for urothelial cancer and cholangiocarcinoma with FGFR fusion (FUS) or/and mutation (MUT). AmoyDx FGFR 1-4 NGS Panel (FGFR-P) was developed for FGFR alts detection based on both DNA and RNA. The goal of this study is to validate and assess the performance of FGFR-P in pan-cancer FGFR alts detection by comparing with an AmoyDx comprehensive genomic profiling test (CGP) and a health authority approved DNA-based NGS panel (DNA-P). Methods: Both FGFR-P and CGP are DNA (MUT) and RNA (FUS) based for detecting FGFR alts with optimized bioinformatics pipeline to eliminate baseline noise caused by deamination events, which is commonly found in aged FFPE samples. Cell lines, cell line/patient derived xenografts (CDXs/PDXs) and 397 samples of 26 cancer types (90 samples >10 years) were used for validation of FGFR-P. Total 382 and 50 pan-cancer samples were respectively tested to compare FGFR-P with CGP and DNA-P. Results: To validate accuracy, 36 FFPE samples from cell lines and CDXs/PDXs with known FGFR status (25 FUSs, 5 MUTs, 6 wild-types) were tested by FGFR-P with concordance rate 100%. In clinical sample testing, FGFR-P also showed high agreement with CGP (99.5%) and DNA-P (98.0%). Conflicting result confirmed by FISH revealed 1 FUS missed by DNA-P but detected by FGFR-P, which demonstrated advantage of FGFR alts detection by DNA+RNA. In addition, an optimized bioinformatics pipeline by mimic samples with deamination events effectively filtered out C:G>T:A false positive signals. FGFR-P achieved high success rate in testing pan-tumor samples (89.9%) including samples >10 years (75.6%). Conclusions: FGFR-P provides a novel opportunity to identify FGFR alt pan-cancer patients using a robust DNA+RNA NGS platform, which shows high success rate even in aged samples and will be a potent tool for sensitive and reliable detection of FGFR alts for clinical diagnostics. CGP FGFR-P MUT Positive Negative Total Positive 29 0 29 Negative 1 194 195 Total 30 194 224 FUS Positive Negative Total Positive 20 1 21 Negative 0 137 137 Total 20 138 158 The overall percent agreement 99.5% Citation Format: Min Qing, Xuejun Chen, Wenqing Su, Xiaofang Zhuo, Ting Shen, Chengjuan Xiong, Xuesong Lyu, Renee Tate, Qibiao Wu, Longen Zhou, Shibu Thomas, Wangwang Ning, Jianqing Wang, Huihui Yan, Zhiqiang Yin, Zhan Huang, Yaxin Xue, Changbin Zhu. Identification of fibroblast growth factor receptors (FGFRs) alterations (alts) at DNA and RNA-level by one-step next-generation sequencing (NGS) panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1035.
Neoadjuvant chemoimmunotherapy has a promising effect on locally advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers robustly predicting therapeutic response are still lacking.
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