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The increasing incidence of early-onset colorectal cancer (age <50 years; EOCRC) shows a dramatic growing trend globally, while late-onset colorectal cancer (LOCRC) is gradually decreasing. We aimed to characterise the distinct mutational landscape of EOCRC in an effort to inform age-specific clinical management. In this observational study, we analysed whole-exome sequencing and clinical-grade targeted sequencing data from seven cohorts (the Memorial Sloan Kettering Cancer Center [MSKCC] cohort [the USA], the Leiden University Medical Center cohort [the Netherlands], the Nigerian African Research Group for Oncology [ARGO] cohort [Nigeria], the Genomics Evidence Neoplasia Information Exchange [GENIE] Project [Canada, France, Spain, and the USA], the Sun Yat-sen University Cancer Center (SYSUCC) cohort [China], the Asan Medical Center cohort [South Korea], and the Fudan University Shanghai Cancer Center–Colorectal Cancer [FUSCC-CRC] cohort [China]) across Canada, China, France, Nigeria, South Korea, Spain, the Netherlands, and the USA. Eligible patients were aged 18 years or older with a confirmed diagnosis of colorectal adenocarcinoma or mucinous adenocarcinoma. Samples were categorised into hypermutated (tumour mutational burden [TMB] >15 mutations per megabase) and non-hypermutated (TMB ≤15 mutations per megabase) groups. We evaluated the TMB difference between EOCRC and LOCRC using gamma regression and compared genomic mutation data between EOCRC and LOCRC using multiple logistic regression and pathway enrichment analysis. The primary study objective was to compare genomic mutational patterns between EOCRC and LOCRC, stratified by TMB groups. Between Jan 1 and Dec 31, 2024, 17 133 tumour samples from patients with colorectal cancer in eight countries were analysed (Canada [n=218], China [n=3009], France [n=62], Nigeria [n=64], South Korea [n=44], Spain [n=250], the Netherlands [n=281], and the USA [n=13 205]). Among 17 133 patients, 9452 (55·2%) were male, 7681 (44·8%) were female, 10 174 (59·4%) were White, 3904 (22·8%) were Asian or Pacific Islander, 983 (5·7%) were Black, and 4983 (29·1%) had EOCRC. In hypermutated colorectal cancer, EOCRC exhibited a significantly higher TMB compared with LOCRC (mean ratio 1·11 [95% CI 1·06–1·16]; p<0·0001). In non-hypermutated colorectal cancer, EOCRC showed a significantly lower TMB than LOCRC after adjusting for skewness (mean ratio 2·92 [95% CI 2·88–2·96]; p<0·0001). In hypermutated colorectal cancer, a total of 23 genes, including APC (EOCRC 464 [75·0%] of 619 vs LOCRC 891 [58·6%] of 1521; odds ratio [OR] 2·00 [95% CI 1·59–2·51]; adjusted p<0·0001), KRAS (EOCRC 331 [53·3%] of 621 vs LOCRC 488 [32·0%] of 1526; OR 2·35 [95% CI 1·91–2·89]; adjusted p<0·0001), and CTNNB1 (EOCRC 196 [31·6%] of 621 vs LOCRC 274 [18·0%] of 1526; OR 2·15 [95% CI 1·70–2·72]; adjusted p<0·0001), and TCF7L2 (EOCRC 294 [51·2%] of 574 vs LOCRC 489 [35·0%] of 1398; OR 2·01 [95% CI 1·62–2·50]; adjusted p<0·0001), displayed elevated mutation frequencies in EOCRC compared with LOCRC, whereas only BRAF (EOCRC 97 [15·6%] of 621 vs LOCRC 674 [44·2%] of 1526; OR 0·27 [95% CI 0·21–0·35]; adjusted p<0·0001) and RNF43 (EOCRC 225 [39·3%] of 573 vs LOCRC 778 [53·9%] of 1444; OR 0·61 [95% CI 0·49–0·76]; adjusted p=0·0015) were less frequently mutated in EOCRC than in LOCRC. In non-hypermutated colorectal cancer, only TP53 (EOCRC 3468 [79·5%] of 4362 vs LOCRC 7825 [73·7%] of 10 624; OR 1·37 [95% CI 1·25–1·50]; adjusted p<0·0001) showed a higher mutation frequency in EOCRC, while nine genes had lower mutation frequencies, including BRAF (EOCRC 274 [6·3%] of 4362 vs LOCRC 909 [8·6%] of 10 624; OR 0·70 [95% CI 0·60–0·81]; adjusted p=0·00024) and KRAS (EOCRC 1794 [41·1%] of 4362 vs LOCRC 4840 [45·6%] of 10624; OR 0·83 [95% CI 0·77–0·89]; adjusted p=0·00019). Within hypermutated colorectal cancer, younger patients exhibited a higher mutational burden than older patients. Our study reveals an abnormal accumulation of distinct somatic mutations in hypermutated EOCRC, the pattern of which might be contributing to the alarming rise in the incidence of EOCRC over the past decades. Our results support the need for EOCRC-specific molecular profiling to guide clinical practice. National Natural Science Foundation of China and the Shanghai Science and Technology Development Fund.

Background Large immunogenomic analyses have demonstrated the prognostic role of the functional orientation of the tumor microenvironment in adult solid tumors, this variable has been poorly explored in the pediatric counterpart. Methods We performed a systematic analysis of public RNAseq data (TARGET) for five pediatric tumor types (408 patients): Wilms tumor (WLM), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response. We also performed gene set enrichment analysis (ssGSEA) and clustered more than 100 well characterized immune traits to define immune subtypes and compared their outcome. Results A higher ICR score was associated with better survival in OS and high risk NBL without MYCN amplification but with poorer survival in WLM. Clustering of immune traits revealed the same five principal modules previously described in adult tumors (TCGA). These modules divided pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival, characterized by low enrichment of the wound healing signature, high Th1, and low Th2 infiltration, while the reverse was observed in S4. Upregulation of the WNT/Beta-catenin pathway was associated with unfavorable outcomes and decreased T-cell infiltration in OS. Conclusions We demonstrated that extracranial pediatric tumors could be classified according to their immune disposition, unveiling similarities with adults’ tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.

NY-ESO-1 or New York esophageal squamous cell carcinoma 1 is a well-known cancer-testis antigen (CTAs) with re-expression in numerous cancer types. Its ability to elicit spontaneous humoral and cellular immune responses, together with its restricted expression pattern, have rendered it a good candidate target for cancer immunotherapy. In this review, we provide background information on NY-ESO-1 expression and function in normal and cancerous tissues. Furthermore, NY-ESO-1-specific immune responses have been observed in various cancer types; however, their utility as biomarkers are not well determined. Finally, we describe the immune-based therapeutic options targeting NY-ESO-1 that are currently in clinical trial. We will highlight the recent advancements made in NY-ESO-1 cancer vaccines, adoptive T cell therapy, and combinatorial treatment with checkpoint inhibitors and will discuss the current trends for future NY-ESO-1 based immunotherapy. Cancer treatment has been revolutionized over the last few decades with immunotherapy emerging at the forefront. Immune-based interventions have shown promising results, providing a new treatment avenue for durable clinical responses in various cancer types. The majority of successful immunotherapy studies have been reported in liquid cancers, whereas these approaches have met many challenges in solid cancers. Effective immunotherapy in solid cancers is hampered by the complex, dynamic tumor microenvironment that modulates the extent and phenotype of the antitumor immune response. Furthermore, many solid tumor-associated antigens are not private but can be found in normal somatic tissues, resulting in minor to detrimental off-target toxicities. Therefore, there is an ongoing effort to identify tumor-specific antigens to target using various immune-based modalities. CTAs are considered good candidate targets for immunotherapy as they are characterized by a restricted expression in normal somatic tissues concomitant with a re-expression in solid epithelial cancers. Moreover, several CTAs have been found to induce a spontaneous immune response, NY-ESO-1 being the most immunogenic among the family members. Hence, this review will focus on NY-ESO-1 and discuss the past and current NY-ESO-1 targeted immunotherapeutic strategies.

The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus   bromii , associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches. A large, publicly available dataset integrating RNA, whole-exome, T cell receptor and 16S rRNA sequencing from patients with colon cancer enables the discovery of a prognostic score consisting of tumor, immune and microbial features.

Background Lack of Schlafen family member 11 (SLFN11) expression has been recently identified as a dominant genomic determinant of response to DNA damaging agents in numerous cancer types. Thus, several strategies aimed at increasing SLFN11 are explored to restore chemosensitivity of refractory cancers. In this study, we examined various approaches to elevate SLFN11 expression in breast cancer cellular models and confirmed a corresponding increase in chemosensitivity with using the most successful efficient one. As oncogenic transcriptomic downregulation is often driven by methylation of the promotor region, we explore the demethylation effect of 5-aza-2′-deoxycytidine (decitabine), on the SLFN11 gene. Since SLFN11 has been reported as an interferon inducible gene, and interferon is secreted during an active anti-tumor immune response, we investigated the in vitro effect of IFN-γ on SLFN11 expression in breast cancer cell lines. As a secondary approach to pick up cross talk between immune cells and SLFN11 expression we used indirect co-culture of breast cancer cells with activated PBMCs and evaluated if this can drive SLFN11 upregulation. Finally, as a definitive and specific way to modulate SLFN11 expression we implemented SLFN11 dCas9 (dead CRISPR associated protein 9) systems to specifically increase or decrease SLFN11 expression. Results After confirming the previously reported correlation between methylation of SLFN11 promoter and its expression across multiple cell lines, we showed in-vitro that decitabine and IFN-γ could increase moderately the expression of SLFN11 in both BT-549 and T47D cell lines. The use of a CRISPR-dCas9 UNISAM and KRAB system could increase or decrease SLFN11 expression significantly (up to fivefold), stably and specifically in BT-549 and T47D cancer cell lines. We then used the modified cell lines to quantify the alteration in chemo sensitivity of those cells to treatment with DNA Damaging Agents (DDAs) such as Cisplatin and Epirubicin or DNA Damage Response (DDRs) drugs like Olaparib. RNAseq was used to elucidate the mechanisms of action affected by the alteration in SLFN11 expression. In cell lines with robust SLFN11 promoter methylation such as MDA-MB-231, no SLFN11 expression could be induced by any approach. Conclusion To our knowledge this is the first report of the stable non-lethal increase of SLFN11 expression in a cancer cell line. Our results show that induction of SLFN11 expression can enhance DDA and DDR sensitivity in breast cancer cells and dCas9 systems may represent a novel approach to increase SLFN11 and achieve higher sensitivity to chemotherapeutic agents, improving outcome or decreasing required drug concentrations. SLFN11-targeting therapies might be explored pre-clinically to develop personalized approaches.

Human leukocyte antigen G (HLA-G), known as a central protein in providing immune tolerance to the fetus in pregnant women, is also studied for a possible role in tumor development. Many studies have claimed HLA-G as a new immune checkpoint in cancer. Therefore, HLA-G and its receptors might be targets for immune checkpoint blockade in cancer immunotherapy. In order to substantiate that HLA-G is indeed an immune checkpoint in cancer, two important questions need to be answered: (1) To what extent is HLA-G expressed in the tumor by cancer cells? and (2) What is the function of HLA-G in cancer immune evasion? In this review, we discuss these questions. We agree that HLA-G is a potentially new immune checkpoint in cancer, but additional evidence is required to show the extent of intra-tumor and inter-tumor expression. These studies should focus on tumor expression patterns of the seven different HLA-G isoforms and of the receptors for HLA-G. Furthermore, specific roles for the different HLA-G isoforms should be established.

Understanding the biomolecular interactions between graphene and human immune cells is a prerequisite for its utilization as a diagnostic or therapeutic tool. To characterize the complex interactions between graphene and immune cells, we propose an integrative analytical pipeline encompassing the evaluation of molecular and cellular parameters. Herein, we use single-cell mass cytometry to dissect the effects of graphene oxide (GO) and GO functionalized with amino groups (GONH 2 ) on 15 immune cell populations, interrogating 30 markers at the single-cell level. Next, the integration of single-cell mass cytometry with genome-wide transcriptome analysis shows that the amine groups reduce the perturbations caused by GO on cell metabolism and increase biocompatibility. Moreover, GONH 2 polarizes T-cell and monocyte activation toward a T helper-1/M1 immune response. This study describes an innovative approach for the analysis of the effects of nanomaterials on distinct immune cells, laying the foundation for the incorporation of single-cell mass cytometry on the experimental pipeline. Understanding the interaction of nanomaterials and immune cells at the biomolecular level is of great significance in therapeutic applications. Here, the authors investigated the interaction of graphene oxide nanomaterials and several immune cell subpopulations using single-cell mass cytometry and genome-wide transcriptome analysis.

Colon cancer is a heterogeneous disease and consists of various molecular subtypes. Despite advances in high-throughput expression profiling, limitations remain in predicting clinical outcome and assigning specific treatment to individual cases. Tumor-immune interactions play a critical role, with tumors that activate the immune system having better outcome for the patient. The localization of T cells within tumor epithelium, to enable direct contact, is essential for antitumor function, but bulk DNA/RNA sequencing data lacks spatial distribution information. In this study, we provide spatial T cell tumor distribution and connect these data with previously determined genomic data in the AC-ICAM colon cancer patient cohort. Colon cancer patients (n=90) with transcriptome data available were selected. We used a custom multiplex immunofluorescence assay on colon tumor tissue sections for quantifying T cell subsets spatial distribution in the tumor microenvironment, in terms of cell number, location, mutual distance, and distance to tumor cells. Statistical analyses included the previously determined Immunologic Constant of Rejection (ICR) transcriptome correlation and patient survival, revealing potential prognostic value in T cell spatial distribution. T cell phenotypes were characterized and CD3 CD8 FoxP3 T cells were found to be the predominant tumor-infiltrating subtype while CD3 FoxP3 T cells and CD3 CD8 T cells showed similar densities. Spatial distribution analysis elucidated that proliferative T cells, characterized by Ki67 expression, and Granzyme B-expressing T cells were predominantly located within the tumor epithelium. We demonstrated an increase in immune cell density and a decrease in the distance of CD3 CD8 T cells to the nearest tumor cell, in the immune active, ICR High, immune subtypes. Higher densities of stromal CD3 FoxP3 T cells showed enhanced survival outcomes, and patients exhibited superior clinical benefits when greater spatial distances were observed between CD3 CD8 FoxP3 or CD3 CD8 T cells and CD3 FoxP3 T cells. Our study's in-depth analysis of the spatial distribution and densities of major T cell subtypes within the tumor microenvironment has provided valuable information that paves the way for further research into the intricate relationships between immune cells and colon cancer development.

The immune system has a substantial effect on colorectal cancer (CRC) progression. Additionally, the response to immunotherapeutics and conventional treatment options (e.g., chemotherapy, radiotherapy and targeted therapies) is influenced by the immune system. The molecular characterization of colorectal cancer (CRC) has led to the identification of favorable and unfavorable immunological attributes linked to clinical outcome. With the definition of consensus molecular subtypes (CMSs) based on transcriptomic profiles, multiple characteristics have been proposed to be responsible for the development of the tumor immune microenvironment and corresponding mechanisms of immune escape. In this review, a detailed description of proposed immune phenotypes as well as their interaction with different therapeutic modalities will be provided. Finally, possible strategies to shift the CRC immune phenotype towards a reactive, anti-tumor orientation are proposed per CMS.

Background The balance between immune-stimulatory and immune-suppressive mechanisms in the tumour microenvironment is associated with tumour rejection and can predict the efficacy of immune checkpoint-inhibition therapies. Methods We consider the observed differences between the transcriptional programmes associated with cancer types where the levels of immune infiltration predict a favourable prognosis versus those in which the immune infiltration predicts an unfavourable prognosis and defined a score named M ediators of I mmune R esponse A gainst C ancer in so L id micro E nvironments (MIRACLE). MIRACLE deconvolves T cell infiltration, from inhibitory mechanisms, such as TGFβ, EMT and PI3Kγ signatures. Results Our score outperforms current state-of-the-art immune signatures as a predictive marker of survival in TCGA ( n  = 9305, HR: 0.043, p value: 6.7 × 10 −36 ). In a validation cohort ( n  = 7623), MIRACLE predicts better survival compared to other immune metrics (HR: 0.1985, p value: 2.73 × 10 −38 ). MIRACLE also predicts response to checkpoint-inhibitor therapies ( n  = 333). The tumour-intrinsic factors inversely associated with the reported score such as EGFR, PRKAR1A and MAP3K1 are frequently associated with immune-suppressive phenotypes. Conclusions The association of cancer outcome with the level of infiltrating immune cells is mediated by the balance of activatory and suppressive factors. MIRACLE accounts for this balance and predicts favourable cancer outcomes.