Over the last decade, the annual Immunorad Conference, held under the joint auspicies of Gustave Roussy (Villejuif, France) and the Weill Cornell Medical College (New-York, USA) has aimed at exploring the latest advancements in the fields of tumor immunology and radiotherapy-immunotherapy combinations for the treatment of cancer. Gathering medical oncologists, radiation oncologists, physicians and researchers with esteemed expertise in these fields, the Immunorad Conference bridges the gap between preclinical outcomes and clinical opportunities. Thus, it paves a promising way toward optimizing radiotherapy-immunotherapy combinations and, from a broader perspective, improving therapeutic strategies for patients with cancer. Herein, we report on the topics developed by key-opinion leaders during the 7th Immunorad Conference held in Paris-Les Cordeliers (France) from September 27th to 29th 2023, and set the stage for the 8th edition of Immunorad which will be held at Weill Cornell Medical College (New-York, USA) in October 2024.

Immune checkpoint blockade (ICB) therapies have demonstrated significant clinical efficacy in immune-infiltrated tumors such as melanoma and non-small cell lung cancer. However, "cold tumors"-including ovarian cancer, pancreatic cancer, and gliomas-exhibit insufficient immune infiltration, leading to poor therapeutic responses to ICBs and limited improvement in patient prognosis. Recent studies have shown that tumor-associated tertiary lymphoid structures (TLSs) can induce strong local immune responses within the tumor microenvironment (TME), serving as important biological markers for predicting ICB therapy efficacy. Notably, preclinical and clinical studies on cold tumors have confirmed that TLSs can potently enhance ICB efficacy through TME remodeling-a breakthrough that has attracted considerable attention. Here, we systematically examine the immunological profile of cold tumors and decipher the mechanistic basis for their impaired immune cell infiltration. We further delineate the distinctive features of tumor-associated TLSs in generating antitumor immunity and establish criteria for their identification. Significantly, we emphasize the unique capability of TLSs to reprogram the immunosuppressive tumor microenvironment characteristic of cold tumors. Based on these insights, we evaluate clinical evidence supporting TLS-mediated enhancement of ICB efficacy and discuss emerging strategies for exogenous TLSs induction.

Artificial intelligence (AI) holds significant promise for improving cancer diagnosis and treatment. Here, we present a foundation AI model for prognosis prediction on the basis of standard hematoxylin and eosin-stained histopathology slides.

In this multinational cohort study, we developed AI models to predict prognosis from histopathology images of patients with GI cancers. First, we trained a foundation model using over 130 million patches from 104,876 whole-slide images on the basis of self-supervised learning. Second, we fine-tuned deep learning models for predicting survival outcomes and validated them across seven cohorts, including 1,619 patients with gastric and esophageal cancers and 2,594 patients with colorectal cancer. We further assessed the model for predicting survival benefit from adjuvant chemotherapy.

The AI models predicted disease-free survival and disease-specific survival with a concordance index of 0.726-0.797 for gastric cancer and 0.714-0.757 for colorectal cancer in the validation cohorts. The models stratified patients into high-risk and low-risk groups, with 5-year survival rates of 49%-52% versus 76%-92% in gastric cancer and 43%-72% versus 81%-98% in colorectal cancer. In multivariable analysis, the AI risk scores remained an independent prognostic factor after adjusting for clinicopathologic variables. Compared with stage alone, an integrated model consisting of stage and image information improved prognosis prediction across all validation cohorts. Finally, adjuvant chemotherapy was associated with improved survival in the high-risk group but not in the low-risk group (treatment-model interaction P = .01 and .006) for stage II/III gastric and colorectal cancer, respectively.

The pathology foundation model can accurately predict survival outcomes and complement clinicopathologic factors in GI cancers. Pending prospective validation, it may be used to improve risk stratification and inform personalized adjuvant therapy.

Immune checkpoint inhibitors (ICIs) represent a groundbreaking advancement in cancer therapy, substantially improving patient survival rates. Our comprehensive research reveals a significant positive correlation between coagulation scores and immune-related gene expression across 30 diverse cancer types. Notably, tumours exhibiting high coagulation scores demonstrated enhanced infiltration of cytotoxic immune cells, including CD8+ T cells, natural killer (NK) cells, and macrophages. Leveraging the TCGA pan-cancer database, we developed the Coagulation.Sig model, a sophisticated predictive framework utilising a coagulation-related genes (CRGs) to forecast immunotherapy outcomes. Through rigorous analysis of ten ICI-treated cohorts, we identified and validated seven critical CRGs: BIRC2, HMGB1, STAT2, IFNAR1, BID, SPATA2, IL33 and IFNG, which form the foundation of our predictive model. Functional analyses revealed that low-risk tumours characterised by higher immune cell populations, particularly CD8+ T cells, demonstrated superior ICI responses. These tumours also exhibited increased mutation rates, elevated neoantigen loads, and greater TCR/BCR diversity. Conversely, high-risk tumours displayed pronounced intratumor heterogeneity (ITH) and elevated NRF2 pathway activity, mechanisms strongly associated with immune evasion. Experimental validation highlighted BIRC2 as a promising therapeutic target. Targeted BIRC2 knockdown, when combined with anti-PD-1 therapy, significantly suppressed tumour growth, enhanced CD8+ T cell infiltration, and amplified IFN-γ and TNF-α secretion in tumour models. Our findings position the Coagulation.Sig model as a novel, comprehensive approach to personalised cancer treatment, with BIRC2 emerging as both a predictive biomarker and a potential therapeutic intervention point.

The aim of the research is to investigate correlation of immune infiltration between IL-17B and IL-17RB in colorectal cancer (CRC), then provide an experimental basis for clinical diagnostic marker screening of CRC.

Gene expression levels were assessed via TIMER and GEPIA databases, protein expression through the Human Protein Atlas (HPA), clinicopathological correlations and prognosis via UALCAN and KM-Plotter, respectively. Mutation analysis was conducted using cBioPortal, immune cell infiltration via TIMER, and hub genes were identified through protein-protein interaction (PPI) networks. Biological functions and pathways were elucidated with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, the expression of IL-17B, IL-17RB, and associated inflammatory cells in CRC were analyzed using immunohistochemical staining and special staining technique.

Bioinformatics analysis showed that IL-17B gene and protein expression levels decreased, while IL-17RB expression increased in CRC. IL-17B expression was affected by gender, body weight, histology, lymph node status, and tumour grade. Overexpression of IL-17B was negatively correlated with progression-free survival in CRC. IL-17B is involved in phosphatidylinositol 3-kinase/AKT signaling, vascular development, and other processes. IL-17B is associated with mitochondrial gene expression, regulation of mRNA metabolism, amino acid metabolism and other processes, as well as phosphatidylinositol-binding and liganding. Inositol 3-kinase/AKT signalling and vascular development. IL-17B was negatively correlated with mitochondrial gene expression, regulation of mRNA metabolism, amino acid metabolism and other processes as well as with molecular functions such as phosphatidylinositol binding and ligase activity. IL-17RB expression was correlated with the clinicopathological features described above and decreased with tumour progression. High levels of IL-17RB were associated with improved overall survival and immune cell infiltration. The key genes of IL-17RB are mainly involved in DNA damage, metabolism, checkpoint signaling and regulation of replication. Immunohistochemical staining results showed that the expression of IL-17B and IL-17RB reduced in CRC, compared to normal colon tissue (p < 0.05). IL-17B was positively correlated with CD4+ T lymphocyte and mast cell infiltration. IL-17RB was positively correlated with CD4+ T lymphocyte infiltration and negatively correlated with CD20+ B lymphocyte infiltration.

The expression of IL-17RB in CRC decreased with increasing tumour stage, and high levels of IL-17RB predicted a better prognosis, suggesting that its decreased expression was associated with disease progression. Therefore, IL-17RB may be a biomarker for assessing the prognosis of CRC. Meanwhile, IL-17B was positively correlated with CD4+ T lymphocyte and mast cell infiltration, and its overexpression was negatively correlated with recurrence-free survival, IL-17B and IL-17RB may affect CRC through different pathway mechanisms.

Breast cancer (BC) is the leading cancer among women globally, which has the highest incidence and mortality rate in over a hundred countries. This study was intended to discover a new prognostic biomarker, facilitating personalized treatment approaches.

RNA sequencing data from The Cancer Genome Atlas database and Gene Expression Omnibus database were utilized to download to evaluate expression levels and prognostic significance of Keratin 14 (KRT14). Methylation of KRT14 was also assessed. The CIBERSORT and single-sample gene set enrichment analysis algorithms were applied to explore the connection between KRT14 and the tumor microenvironment. Primary drugs' sensitivity and potential small molecule therapeutic compounds were analyzed through the "pRRophetic" R package and the Connectivity Map. The prognostic value of KRT14 was additionally corroborated through a comparison of protein levels in peritumoral and cancerous tissues via immunohistochemistry. Moreover, an immune-related prognostic model based on KRT14 was designed to enhance the prediction accuracy for the prognosis of BC patients.

The study found that KRT14 expression was generally downregulated in BC, correlating strongly with poor prognosis. Compared to normal tissues, the methylation level of KRT14 was higher in BC tissues. Lower expression of KRT14 was linked to decreased anti-tumoral immune cells infiltration and increased immunosuppressive cells infiltration. Sensitivity to various key therapeutic drugs was lower in groups with diminished KRT14 expression. In addition, several potential anti-BC small molecule compounds were identified. The model designed in this study significantly enhanced the predictive capability for BC patients compared to predictions based solely on KRT14 expression levels.

Overall, KRT14 was closely correlated with the prognosis in BC, making it a reliable biomarker.

Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide, ranking third in incidence and second in mortality. While immunotherapy has shown promise in patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), its effectiveness in proficient mismatch repair (pMMR) or microsatellite stable (MSS) CRC remains limited. Recent advances highlight the gut microbiota as a potential modulator of anti-tumor immunity. The gut microbiome can significantly influence the efficacy of immune checkpoint inhibitors (ICIs), especially in pMMR/MSS CRC, by modulating immune responses and systemic inflammation. This review explores the role of the gut microbiota in pMMR/MSS CRC, the mechanisms by which it may enhance immunotherapy, and current strategies for microbiota modulation. We discuss the potential benefits of combining microbiota-targeting interventions with immunotherapy to improve treatment outcomes for pMMR/MSS CRC patients.

Colorectal cancer (CRC) is well characterized in terms of genetic mutations and the mechanisms by which they contribute to carcinogenesis. Mutations in APC, TP53, and KRAS are common in CRC, indicating key roles for these genes in tumor development and progression. However, for certain tumors with low frequencies of these mutations that are defined by tumor location and molecular phenotypes, a carcinogenic mechanism dependent on BRAF mutations has been proposed. We here analyzed targeted sequence data linked to clinical information for CRC, focusing on tumors with a high tumor mutation burden (TMB) in order to identify the characteristics of associated mutations, their relations to clinical features, and the mechanisms of carcinogenesis in tumors lacking the major driver oncogenes. Analysis of overall mutation frequencies confirmed that APC, TP53, and KRAS mutations were the most prevalent in our cohort. Compared with other tumors, TMB-high tumors were more frequent on the right side of the colon, had lower KRAS and higher BRAF mutation frequencies as well as a higher microsatellite instability (MSI) score, and showed a greater contribution of a mutational signature associated with MSI. Ranking of variant allele frequencies to identify genes that play a role early in carcinogenesis suggested that mutations in genes related to the DNA damage response (such as ATM and POLE) and to MSI (such as MSH2 and MSH6) may precede BRAF mutations associated with activation of the serrated pathway in TMB-high tumors. Our results thus indicate that TMB-high tumors suggest that mutations of genes related to mismatch repair and the DNA damage response may contribute to activation of the serrated pathway in CRC.

A T cell-inflamed tumor microenvironment is predictive of better prognosis and clinical response to immunotherapy. Proteinase-activated receptor 2 (PAR2), a member of G-protein coupled receptors is involved in inflammatory process and the progression of various cancers. However, the role of PAR2 in modulating the tumor microenvironment remains unclear. Here, we found that PAR2 high-expression was associated with a favorable prognosis in patients with colorectal cancer. Intriguingly, PAR2 expression in human colorectal cancer was mainly confined to tumor cells and was significantly associated with CD8+ T cell infiltration. Tumor-intrinsic PAR2 deficiency blunted antitumor immune responses to promote tumor growth and attenuated the therapeutic efficacy of anti-PD1 in a mouse model of colon cancer. Tumors with downregulated PAR2 showed decreased CD8+ T cell infiltration and impaired effector function. Mechanistically, PAR2 activation in tumor cells induced CXCL9 and CXCL10 production via PI3K/AKT/mTOR signaling, thereby enhancing CD8+ T cell recruitment in the tumor microenvironment. In addition, PAR2 was essential for dendritic cell activation and differentiation towards conventional type 1 subset. PAR2 deficiency in dendritic cells markedly impaired their ability to prime CD8+ T cells and control tumor growth in vivo. Thus, our findings identify new roles for PAR2 in promoting antitumor immunity and provide a promising target to improve immunotherapy efficacy in colorectal cancer.

This study aimed to decipher the intricate interplay between the immune landscape and CRC pathogenesis, elucidating how distinct immunophenotypes causally influence disease susceptibility and stratify patient outcomes.

We obtained the immunocyte phenotypes and CRC data from their respective genome-wide association studies. The primary analysis used the inverse variance weighting (IVW) method. We also simultaneously employed MR-Egger, weighted mode, simple mode, and weighted median approaches to strengthen the findings. Consensus clustering stratified 619 TCGA CRC patients by immunome expression. Functional assays examined the tumor suppressor GPD1L.

The IVW MR analysis identified 17 immunocyte phenotypes positively potentially associated with increased CRC risk (P < 0.05, OR > 1), and 18 phenotypes negatively potentially associated with decreased CRC risk (P < 0.05, OR < 1). These associations were not confounded by heterogeneity or horizontal pleiotropy (P > 0.05). Reverse MR analysis further revealed 4 additional immunocyte phenotypes positively potentially associated with CRC (P < 0.05, OR > 1). Clustering resolved prognostic C1/C2 subtypes dependent on coordinated immunophenotypic programs. GPD1L knockdown promoted CRC cell proliferation.

Genetic interrogation delineated causal immunome-CRC relationships at single-cell resolution. Immune-stratified CRC subtyping stratified patient outcomes. GPD1L exhibited tumor-suppressive functions. Our findings establish an integrated immunogenomic framework elucidating CRC pathogenesis with implications for precision immunotherapies.

Immune checkpoint inhibitors (ICIs) have improved outcomes of patients with many different cancers. These antibodies target molecules such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4) which normally function to limit immune activity. Treatment with ICIs reactivates T cells to destroy tumor cells in a highly specific manner, which in some patients, results in dramatic remissions and durable disease control. Over the last decade, much effort has been directed at characterizing factors that drive efficacy and resistance to ICI therapy. Food and Drug Administration (FDA)-approved biomarkers for ICI therapy have facilitated more judicious treatment of cancer patients and transformed the field of precision oncology. Yet, adaptive immunity against cancers is complex, and newer data have revealed the potential utility of other biomarkers. In this review, we discuss the utility of currently approved biomarkers and highlight how emerging biomarkers can further improve the identification of patients who benefit from ICIs.

Qingjie Fuzheng Granules (QFG), a herbal formula, has been employed as an adjuvant therapy for colitis-associated colorectal cancer (CAC), yet the underlying mechanisms by which QFG operates remain unclear.

The aim of this study is to investigate whether the potential mechanism of QFG against CAC is associated with macrophage polarization.

Non-targeted metabolomics and molecular docking assessed potential compounds of QFG to interact with targets associated with macrophage polarization. A model of AOM/DSS-induced CAC mice was established to analyze the effects of QFG on macrophage polarization using flow cytometry and immunohistochemical staining. In vitro experiments involved models of Ana-1 macrophages, either induced by varying QFG concentrations or with MD2 knockdown, to analyze M1-like phenotype. Meanwhile, M2-like macrophages models induced by IL-4 or culture supernatant of CT26 cells were utilized to assess the effects of QFG on M2-like macrophages. Finally, the mRNA expression of M1-like phenotype related to TLR4 pathways and the protein expression in IL-4R-mediated pathways were analyzed using RT-qPCR and Western blot, respectively.

Molecular docking confirmed the presence of binding sites between the ingredients of QFG and IL-4R or TLR4/MD2 receptor complex. QFG could induce a shift in macrophages towards an M1-like phenotype while inhibiting an M2-like phenotype in the colon with CAC mice and Ana-1 macrophages. QFG resulted in the upregulation of iNOS, IL-6, IL-1β, and TNF-α mRNA expression, which could be counteracted by TAK242, SR11302, INH14, PDTC, and LY294002, or by the knockdown of MD2. Meanwhile, QFG inhibited IL-4R-induced phosphorylation of STAT 6 and Akt.

Various monomer components within QFG can bind to MD2 or IL-4R, respectively, thereby inducing macrophages towards an M1-like phenotype through TLR4-mediated NF-κB, MAPK, and PI3K/Akt pathway activation, or inhibiting macrophages towards an M2-like phenotype via IL-4R-mediated JAKs pathway inhibition, ultimately exerting an inhibitory effect on the occurrence and development of CAC.

To analyze the expression levels, clinical significance, Immune infiltration and prognostic value of PRSS53 (Protease Serine 53) in clear cell renal cell carcinoma (ccRCC) using bioinformatics methods.

Data on PRSS53 in ccRCC were extracted from databases and platforms, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), The Gene Expression Omnibus (GEO), Xiantao Academic Tool, Human Protein Atlas (HPA) and so on. We analyzed the relationship between PRSS53 expression and the clinical and pathological characteristics, diagnosis, immune infiltration and prognosis in ccRCC patients. Additionally, immunohistochemical analysis was performed on 9 pairs of ccRCC patient samples.

PRSS53 was significantly upregulated in ccRCC and was closely associated with the TNM stage and histological grade of ccRCC. Receiver operating characteristic (ROC) curve analysis demonstrated the excellent diagnostic performance of PRSS53 in ccRCC (AUC = 0.928). Patients with high PRSS53 expression exhibited lower overall survival (OS) and disease-specific survival (DSS). Gene set enrichment analysis (GSEA) revealed that PRSS53 is involved in cellular functions such as anchored component of membrane, basement membrane and RNA-binding involved in post-transcriptional gene silencing. Single-sample GSEA (ssGSEA) indicated a positive correlation between PRSS53 expression and T helper cells infiltration levels, and a negative correlation with T gamma delta (Tgd) cell infiltration. PRSS53 was predominantly expressed in renal proximal tubules. The immunohistochemical results and HPA database showed that PRSS53 protein expression was significantly lower in clinical ccRCC tissues  compared to normal tissues.

PRSS53 is a new prognostic biomarker and potential therapeutic target for ccRCC.

The density of tumor-infiltrating lymphocytes (TILs) serves as a valuable indicator for predicting anti-tumor responses, but its broad impact across various types of cancers remains underexplored. We introduce TILScout, a pan-cancer deep-learning approach to compute patch-level TIL scores from whole slide images (WSIs). TILScout achieved accuracies of 0.9787 and 0.9628, and AUCs of 0.9988 and 0.9934 in classifying WSI patches into three categories-TIL-positive, TIL-negative, and other/necrotic-on validation and independent test sets, respectively, surpassing previous studies. The biological significance of TILScout-derived TIL scores across 28 cancers was validated through comprehensive functional and correlational analyses. A consistent decrease in TIL scores with an increase in cancer stage provides direct evidence that the lower TIL content may stimulate cancer progression. Additionally, TIL scores correlated with immune checkpoint gene expression and genomic variation in common cancer driver genes. Our comprehensive pan-cancer survey highlights the critical prognostic significance of TILs within the tumor microenvironment.

In clinical practice, lymph node status has an important impact on colon cancer (CC) management and treatment. The role of the tumor microenvironment collagen score and immunoscore in colon cancer lymph node metastasis remains unknown.

A total of 249 CC patients who underwent laparoscopic-assisted D3 lymphadenectomy from June 2016 to May 2019 were included. The patients' clinicopathological data were collected retrospectively. A total of 142 collagen features were extracted by multiphoton imaging and collagen quantification. A collagen score was constructed using a LASSO logistic regression model. Antibodies against CD3 and CD8 were used for immunostaining. The immunoscore was constructed based on the mean densities of CD3 + and CD8 + T cells both in the tumor center and invasion margin on imaging.

The lymph node metastasis rate among colon cancer patients was 42.2% (105/249). The multivariate analysis indicated that lymphatic invasion (OR: 3.892, 95% CI: 1.784-8.491, p = 0.001), vascular invasion (OR, 3.234, 95% CI: 1.544-6.776); p = 0.002), mucus adenocarcinoma and signet-ring cell carcinoma (OR: 2.990, 95% CI: 1.413-6.328, p = 0.004), the collagen score (OR: 6.304, 95% CI: 2.145-18.527, p = 0.001) and the immunoscore [intermediate group (OR, 2.473; 95% CI, 1.192-5.130; p = 0.015); low group (OR, 5.877; 95% CI, 2.423-14.257; p < 0.01)] were independent risk factors for colon cancer lymph node metastasis. The newly developed model comprising these five independent predictors showed good discrimination with an AUROC of 0.809 (95% CI: 0.755-0.862). The new model performed significantly better than the traditional clinicopathological model [AUROC: 0.715 (95% CI: 0.649-0.780), p < 0.001].

The tumor microenvironment collagen score and immunoscore are associated with colon cancer lymph node metastasis.

The rapid increase in colorectal cancer (CRC) cases recently has highlighted the need to use predictive biomarkers to guide therapeutic approaches. Current studies have focused on the tumor-infiltrating lymphocytes present in the tumor microenvironment (TME), in which cytotoxic T cell activation and the amount are associated with CRC patient prognosis. The T cell receptor (TCR) is essential for antigen recognition and T cell identification, playing a central role in cancer immunotherapy. The T cell status reflects TCR diversity or clonality, known as the TCR repertoire. Accordingly, analyzing the TCR repertoire dynamics may help predict the immunological circumstances of the TME in a timely way. In this review, we summarize the TCR repertoire-related knowledge, including its potential use as predictive biomarkers in CRC. The intratumoral TCR repertoire is restricted in CRC patients compared with healthy individuals, as well as in peripheral blood. Patients with deficient mismatch repair display more restriction than those with proficient mismatch repair. Importantly, a higher TCR diversity before treatment and a decrease following treatment may indicate a good response and a better clinical outcome in CRC patients. The future use of TCR repertoire sequencing technology combined with artificial intelligence-based analysis is a potential strategy for CRC therapeutic decision making.

Ganoderma tsugae, a traditional medicinal mushroom, exhibits anti-tumor properties; however, the effects of its polysaccharide on anti-colorectal cancer remain undetermined. Herein, a fucogalactan of Ganoderma tsugae (GTP-a2) was isolated and purified from its fruiting body. The molecular weight of GTP-a2 is 7.056 kDa, consisting of →6)-α-D-Galp-(1→ backbone with branches of α-L-Fucp-(1→, which is attached at C2. Subsequently, the anti-colorectal cancer activity and potential mechanism of GTP-a2 were investigated in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated colorectal cancer (CAC) mice. GTP-a2 reduced colorectal tumor numbers and suppressed tumor development. Metabolite analysis of the colon revealed that GTP-a2 altered cancer-related metabolites, notably increasing ophiobolin A level. Combined with proteomics and biochemical detection data revealed that GTP-a2 regulated the levels of Aldh1a3 through the mammalian target of rapamycin (mTOR)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in vivo and in vitro. Additionally, GTP-a2 regulated immune function by inhibiting macrophage polarization to M1-like phenotype. These results suggest the potential application of GTP-a2 as a therapeutic agent for CAC.

Prognostic value of T-cells between primary colorectal cancer (pCRC) and its paired synchronous and metachronous liver metastasis (LM) is underinvestigated and is the subject of the present study. We enrolled into this retrospective cohort study patients, who underwent resection of both pCRC and synchronous LM (N = 55) or metachronous LM (N = 44). After immunohistochemical staining for CD3+, CD8+, and CD45R0+ whole slides were scanned and T-cell densities were quantified using QuPath software in tumor center (TC), inner margin (IM), outer margin (OM), and peritumor zone (PT) of pCRC and LM. High densities of CD8+ T-cells in TC, OM and PT of synchronous LM were associated with longer disease-free survival (DFS). Greater densities of CD3+ T-cells in IM and PT and CD8+ T-cells in IM, OM and PT in synchronous LM over pCRC were associated with longer DFS. Greater densities of CD8+ T-cells in the TC and IM and CD3+ T-cells in the IM of pCRC were found in the metachronous over synchronous group. The first novel finding demonstrated that high density of CD8+ T cells in synchronous LM were associated with favorable outcome. The second finding of high CD8+ cell density in pCRC in metachronous over synchronous CRC may provide a mechanistic basis for the delay of metastatic spread. Both findings could be applied clinically with own reference values.

Sympathetic nerves innervate bone marrow and various immune organs, where norepinephrine-the primary sympathetic neurotransmitter-directly interacts with immune cells that express adrenergic receptors. This article reviewed the key molecular pathways triggered by sympathetic activation and explored how sympathetic activity influences immune cell migration. Norepinephrine serves as a chemoattractant for monocytes, macrophages, and stem cells, promoting the migration of myeloid cells while inhibiting the migration of lymphocytes at physiological concentrations. We also examined the role of immune cell infiltration in cardiovascular diseases and cancer. Evidence suggests that sympathetic activation increases myeloid cell infiltration into target tissues across various cardiovascular diseases, including atherosclerosis, hypertension, cardiac fibrosis, cardiac hypertrophy, arrhythmia, myocardial infarction, heart failure, and stroke. Conversely, inhibiting sympathetic activity may serve as a potential therapeutic strategy to treat these conditions by reducing macrophage infiltration. Furthermore, sympathetic activation promotes macrophage accumulation in cancer tissues, mirroring its effects in cardiovascular diseases, while suppressing T lymphocyte infiltration into cancerous sites. These changes contribute to increased cancer growth and metastasis. Thus, inhibiting sympathetic activation could help to protect against cancer by enhancing T cell infiltration and reducing macrophage presence in tumors.

Background/Objectives: Research on colorectal adenoma is significantly less comprehensive compared to studies on colorectal carcinoma. Although colorectal adenoma is a precursor of the majority of sporadic colorectal cancers, not all adenomas develop into carcinomas. The complex interaction of immune responses in the premalignant tumor microenvironment might be a factor for that. Methods: In this systematic review, we aim to provide a thorough analysis of the current research examining the immune infiltration patterns in sporadic colorectal adenoma tissues in the context of immune cell-based, cytokine-based, and other immunological factor-related changes along the conventional adenoma-carcinoma sequence. The articles included in the review extend up to December 2024 in PubMed and Web of Science databases. Results: Most included studies have shown significant differences in immune cell counts, densities, and cytokine expression levels associated with premalignant colorectal lesions (and/or colorectal cancer). No consensus on the immune-related tendencies concerning CD4+T cells and CD8+T cells was reached. Decreasing expression of mDCs and plasma and naïve B cells were detected along the ACS. The increased density of tissue eosinophils in the adenoma tissue dramatically diminishes after the transition to carcinoma. As the adenoma progresses, the increasing expression of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-21, IL-23, IL-33, and TGF-β and decreasing levels of IL-12A, IL-18, IFN-γ, and TNFα cytokines in the invasive carcinoma stage is being detected. The over-expression of COX-2, PD-1/PD-L1, CTLA-4, and ICOS/ICOSLG in the colorectal adenomatous and cancerous tissues was also observed. Conclusions: Further studies are needed for a better understanding of the whole picture of colorectal adenoma-associated immunity and its impact on precancerous lesion's potential to progress.

This study aimed to elucidate the clinical outcomes of patients with pathologic T3 (pT3) and pathologic T4 (pT4) tumors who underwent radical resection with multivisceral resection (MVR) and to assess the prognostic significance of MVR in locally advanced colorectal cancers (CRCs) in pT3 and pT4 tumors.

This multicenter retrospective analysis evaluated the characteristics, clinicopathologic stages, perioperative factors, and clinical outcomes of patients who underwent primary colorectal resection. Patients were divided into 4 groups: those with a pT3 tumor who did not undergo MVR (pT3 - MVR; n = 1108), those with a pT3 tumor who underwent MVR (pT3 + MVR; n = 56), those with a pT4 tumor who did not undergo MVR (pT4 - MVR; n = 306), and those with a pT4 tumor who did underwent MVR (pT4 + MVR; n = 123). Univariate and multivariate regression analyses were performed to identify risk factors for recurrence.

The pT3 + MVR group exhibited a higher 5-year recurrence rate than the pT3 - MVR group, with recurrence rates similar to those of the pT4 - MVR or pT4 + MVR groups (pT3 - MVR, 17.4%; pT3 + MVR, 31.6%; pT4 - MVR, 33.4%; pT4 + MVR, 35.1%). Multivariate analysis identified MVR as an independent risk factor for recurrence, particularly peritoneal dissemination, in pT3 tumors, whereas MVR had less effect on recurrence in pT4 tumors.

pT3 tumors requiring MVR had a higher recurrence rate than pT4 tumors. The surgeon's clinical assessment of potential T4 tumors requiring MVR at the time of surgery was an important prognostic indicator in advanced CRC.

Background/Objectives: Although immunotherapy is the primary treatment option for intermediate-stage hepatocellular carcinoma (HCC), its efficacy varies. This study aimed to identify non-invasive imaging biomarkers predictive of the immunoscore linked to dynamic contrast-enhanced computed tomography (CECT). Methods: We performed immunohistochemical staining with CD3+ and CD8+ antibodies and counted the positive cells in the invasive margin (IM) and central tumor (CT), converting them to an immunoscore of 0 to 4 points. We assessed the dynamic CECT findings obtained from 96 patients who underwent hepatectomy for HCC and evaluated the relationship between dynamic CECT findings and immunoscores. For validation, we assessed the treatment effects on 81 nodules using the Response Evaluation Criteria in Solid Tumors in another cohort of 41 patients who received combined immunotherapy with atezolizumab and bevacizumab (n = 27) and durvalumab and tremelizumab (n = 14). Results: HCCs with peritumoral enhancement in the arterial phase (p < 0.001) and rim APHE (p = 0.009) were associated with the immunoscore in univariate linear regression analysis and peritumoral enhancement in the arterial phase (p = 0.004) in multivariate linear regression analysis. The time to nodular progression in HCCs with peritumoral enhancement in the arterial phase was significantly longer than that in HCCs without this feature (p < 0.001). Conclusions: We identified HCCs with peritumoral enhancement in the arterial phase as a noninvasive imaging biomarker to predict immune-inflamed HCC with a high immunoscore tendency. These HCCs were most likely to respond to combined immunotherapy.

Gastric cancer (GC) is a pressing global health concern, with prognosis intricately linked to the tumour stage and tumour microenvironment, especially, the presence of immune cells. Notably, CD8 + T cells play a pivotal role in the anti-tumour immune response, prompting investigations into their correlation with GC survival. This study aimed to investigate the intricate interplay between CD8 + T cells, particularly within the context of CXCR6, and survival outcomes in patients with GC.

Utilising datasets from The Cancer Genome Atlas, Gene Expression Omnibus, and Tumor Immune Dysfunction and Exclusion, the study employed xCell and Weighted Gene Co-expression Network Analysis to assess CD8 + T cell infiltration and identify key gene clusters. The prognostic significance of CXCR6 was evaluated via immunohistochemical staining of a GC tissue microarray.

High CD8 + T cell infiltration correlated with improved survival in patients with GC. CXCR6 was identified as a prognostic gene and its expression was predominantly observed in CD8 + T cells. CXCR6 expression positively correlated with improved overall and disease-free survival. Furthermore, CXCR6 expression was associated with an immunoreactive microenvironment.

This study established that high CD8 + T-cell infiltration is related to CXCR6 expression, making it a key factor in predicting a favorable GC prognosis. The role of CXCR6 in shaping the tumour microenvironment and its potential utility in immunotherapy response prediction highlights its significance in GC management.

Current prognostic and predictive biomarkers for lung adenocarcinoma (LUAD) predominantly rely on unimodal approaches, limiting their characterization ability. There is an urgent need for a comprehensive and accurate biomarker to guide individualized adjuvant therapy decisions.

In this retrospective study, data from patients with resectable LUAD (stage I-III) were collected from two hospitals and a publicly available dataset, forming a training dataset (n=223), a validation dataset (n=95), a testing dataset (n=449), and the non-small cell lung cancer (NSCLC) Radiogenomics dataset (n=59). Tumor and peritumor scores were constructed from preoperative CT radiomics features (shape/intensity/texture). An immune score was derived from the density of tumor-infiltrating lymphocytes (TILs) within the cancer epithelium and stroma on hematoxylin and eosin-stained whole-slide images. A clinical score was constructed based on clinicopathological risk factors. A Cox regression model was employed to integrate these scores, thereby constructing a multimodal nomogram to predict disease-free survival (DFS). The adjuvant chemotherapy benefit rate was subsequently calculated based on this nomogram.

The multimodal nomogram outperformed each of the unimodal scores in predicting DFS, with a C-index of 0.769 (vs 0.634-0.731) in the training dataset, 0.730 (vs 0.548-0.713) in the validation dataset, and 0.751 (vs 0.660-0.692) in the testing dataset. It was independently associated with DFS after adjusting for other clinicopathological risk factors (training dataset: HR=3.02, p<0.001; validation dataset: HR=2.33, p<0.001; testing dataset: HR=2.03, p=0.001). The adjuvant chemotherapy benefit rate effectively distinguished between patients benefiting from adjuvant chemotherapy and those from observation alone (interaction p<0.001). Furthermore, the high-/low-risk groups defined by the multimodal nomogram provided refined stratification of candidates for adjuvant chemotherapy identified by current guidelines (p<0.001). Gene set enrichment analyses using the NSCLC Radiogenomics dataset revealed associations between tumor/peritumor scores and pathways involved in epithelial-mesenchymal transition, angiogenesis, IL6-JAK-STAT3 signaling, and reactive oxidative species.

The multimodal nomogram, which incorporates tumor and peritumor morphology with anti-tumor immune response, provides superior prognostic accuracy compared with unimodal scores. Its defined adjuvant chemotherapy benefit rates can inform individualized adjuvant therapy decisions.

Cancer is the leading cause of death from disease in children. Survival depends not only on surgery, cytostatic drugs, and radiation but also on systemic immune responses. Factors influencing these immune responses in children of different ages and tumor types are unknown. Novel immunotherapies can enhance anti-tumor immune responses, but few children have benefited, and markers of effective responses are lacking. Here, we present a systems-level analysis of immune responses in 191 children within a population-based cohort with diverse tumors and reveal that age and tumor type shape immune responses differently. Systemic inflammation and cytotoxic T cell responses correlate with tumor mutation rates and immune cell infiltration. Clonally expanded T cell responses are rarely detected in blood or tumors at diagnosis but are sometimes elicited during treatment. Expanded T cells are similarly regulated in children and adults with more immunogenic cancers. This research aims to facilitate the development of precision immunotherapies for children with cancer.

Tertiary lymphoid structures (TLS) in cancer are considered ectopic hotspots for immune activation that are similar to lymphoid follicles in secondary lymphoid organs (SLO). This study elucidates shared and TLS/SLO-specific features in pancreatic ductal adenocarcinoma (PDAC). TLS abundance was related to superior survival and T-cell abundance in 110 treatment-naïve PDAC samples, underlining their clinical relevance. Immunofluorescence microscopy identified structural homologies between TLSs and SLOs. In RNA expression analyses of laser-microdissected TLSs and paired SLOs, we observed largely overlapping expression patterns of immune-related gene clusters but distinct expression patterns of T-cell and complement-associated genes. Immune cells in TLS expressed essential markers of germinal center formation. Increased activation of tumor-draining lymph nodes in patients with high numbers of TLSs highlights the relevance of these tumor-related structures to systemic immune response. In line with this, we identified an overlap of expanded B-cell receptor clonotypes in TLSs and SLOs, which suggests a vivid cross-talk between the two compartments. We conclude that combined therapeutic approaches exploiting TLS-mediated antitumor immune responses may improve susceptibility of PDAC to immunotherapy.

Tertiary lymphoid structures (TLS) are lymphocyte aggregates resembling secondary lymphoid organs and are pivotal in cancer immunity. The ambiguous morphological definition of TLS makes it challenging to ascertain their clinical impact on patient survival and response to immunotherapy.

This study aimed to characterize TLS in hematoxylin-eosin tissue sections from lung cancer patients, assessing their occurrence in relation to the local immune environment, mutational background, and patient outcome.

Two pathologists evaluated one whole tissue section from resection specimens of 680 NSCLC patients. TLS were spatially quantified within the tumor area or periphery and further categorized based on the presence of germinal centers (mature TLS). Metrics were integrated with immune cell counts, genomic and transcriptomic data, and correlated with clinical parameters.

TLS were present in 86% of 536 evaluable cases, predominantly in the tumor periphery, with a median of eight TLS per case. Mature TLS were found in 24% of cases. TLS presence correlated positively with increased plasma cell (CD138+) and lymphocytic cell (CD3+, CD8+, FOXP3+) infiltration. Tumors with higher tumor mutational burden exhibited higher numbers of peripheral TLS. The overall TLS quantity was independently associated with improved patient survival, irrespective of TLS maturation status. This prognostic association held true for peripheral TLS but not for tumor TLS.

TLS in NSCLC is common and their correlation with a specific immune phenotype suggests biological relevance in the local immune reaction. The prognostic significance of this scoring system on routine hematoxylin-eosin sections has the potential to augment diagnostic algorithms for NSCLC patients.

Neuroendocrine tumors (NETs) are a diverse group of malignancies that can occur in various organs, with a notable prevalence in the lungs and gastrointestinal tract, which are the focus of this Review. Although NETs are rare in individual organs, their incidence has increased over recent decades, highlighting the urgent need for current classification systems to evolve by incorporating recent advances in the understanding of NET biology. Several omics studies have revealed molecular subtypes, which, when integrated into existing classification frameworks, may provide more clinically relevant insights for patients with NETs. This Review examines recent progress in elucidating the biology of NETs, with a particular emphasis on the tumor microenvironment and cells of origin. The existence of different cells of origin, which may contribute to distinct molecular groups, along with profiles of immune infiltration - despite being generally low - could explain the emergence of more aggressive cases and the potential for metastatic progression. Given the molecular heterogeneity of NETs and the diversity of their microenvironments and different cells of origin, there is an urgent need to develop morphomolecular classification systems. Such systems would make it possible to better characterize tumor progression, identify new therapeutic targets, and, ultimately, guide the development of personalized therapies.

Within the colorectal cancer (CRC) tumour microenvironment, tumour infiltrating lymphocytes (TILs) and tumour cell density (TCD) are recognised prognostic markers. Measurement of TILs and TCD using deep-learning (DL) on haematoxylin and eosin (HE) whole slide images (WSIs) could aid management.

HE WSIs from the primary tumours of 127 CRC patients were included. DL was used to quantify TILs across different regions of the tumour and TCD at the luminal surface. The relationship between TILs, TCD, and cancer-specific survival was analysed.

Median TIL density was higher at the invasive margin than the luminal surface (963 vs 795 TILs/mm2, P = 0.010). TILs and TCD were independently prognostic in multivariate analyses (HR 4.28, 95% CI 1.87-11.71, P = 0.004; HR 2.72, 95% CI 1.19-6.17, P = 0.017, respectively). Patients with both low TCD and low TILs had the poorest survival (HR 10.0, 95% CI 2.51-39.78, P = 0.001), when compared to those with a high TCD and TILs score.

DL derived TIL and TCD score were independently prognostic in CRC. Patients with low TILs and TCD are at the highest risk of cancer-specific death. DL quantification of TILs and TCD could be used in combination alongside other validated prognostic biomarkers in routine clinical practice.

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes across several solid tumour types. Prominent efforts have focused on understanding the anticancer mechanisms of these agents, identifying biomarkers of response and uncovering resistance mechanisms to develop new immunotherapeutic approaches. This research has underscored the crucial roles of the tumour microenvironment and, particularly, tumour-infiltrating lymphocytes (TILs) in immune-mediated tumour elimination. Numerous studies have evaluated the prognostic and predictive value of TILs and the mechanisms that govern T cell dysfunction, fuelled by technical developments in single-cell transcriptomics, proteomics, high-dimensional spatial platforms and advanced computational models. However, questions remain regarding the definition of TILs, optimal strategies to study them, specific roles of different TIL subpopulations and their clinical implications in different treatment contexts. Additionally, most studies have focused on the abundance of major TIL subpopulations but have not developed standardized quantification strategies or analysed other crucial aspects such as their functional profile, spatial distribution and/or arrangement, tumour antigen-reactivity, clonal diversity and heterogeneity. In this Review, we discuss a conceptual framework for the systematic study of TILs and summarize the evidence regarding their biological properties and biomarker potential for ICI therapy. We also highlight opportunities, challenges and strategies to support future developments in this field.

Tumour-infiltrating lymphocytes (TILs) represent a promising cancer biomarker. Different TILs, including CD8+, CD4+, CD3+, and FOXP3+, have been associated with clinical outcomes. However, data are lacking regarding the value of TILs for patients receiving radiation therapy (RT). We conducted a systemic review and meta-analysis of available data evaluating TILs for patients receiving curative-intent therapy including RT.

Eligible studies presented a defined cohort of patients who all received curative-intent therapy, including RT, and also reported the relationship between any TIL score and either tumour response or survival outcomes. After comprehensive search of online databases (PubMed, EMBASE, Cochrane, and Web of Science), 2 authors conducted title, abstract, and whole-text review for quality and risk of bias following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Data from publications that met quality criteria were grouped via (1) TIL analysed, (2) pre- or post-RT TIL assessment, and (3) clinical outcome measured.

Initial search yielded 669 unique studies. Thirty-one studies met quality criteria, of which 20 studied rectal cancer (RC), 4 oesophageal, 3 pancreas, 2 lung, cervical/uterine 1 each. We conducted systematic review and meta-analysis of the RC publications. All except 2 were single-institutional cohort studies. After meta-analysis, the pre-RT epithelial CD8+ (p = 0.04) and stromal FOXP3+ (p = 0.01) counts were associated with survival without disease, while pre-RT epithelial (p = 0.02) and stromal (p = 0.001) FOXP3+ TILs were associated with overall survival. On post-RT analysis, epithelial (p = .04) and stromal (p = 0.02) CD8+ TILs were associated with survival without disease and epithelial CD8+ TILs were associated with overall survival (p = 0.01).Preoperative CD8+ and FOXP3+ TILs were generally associated with tumour response to RT, but meta-analysis was not conducted due to heterogeneity of response measurement techniques.

TILs represent a useful parameter for tumour response and survival outcomes for patients receiving curative-intent therapy, including RT for RC. Future work should aim to standardise TIL measurement and quantification methods and to develop protocols to clarify clinical application of these findings.

Main purpose of this study is to investigate impact of tumor size on risk of lymph node metastasis (LNM) in pT1-stage colorectal cancer (CRC), focusing on colon, rectosigmoid junction, and rectum.

Patients diagnosed with primary pT1 CRC between 2015 and 2019 were selected from National Cancer Database, utilizing International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes. We analyzed factors influencing LNM using uni- and multivariate analysis, then isolated tumor size to study its impact on LNM.

In this study of 27,649 pT1-stage tumor patients, we found that 10 ​% of colon, 16 ​% of rectosigmoid junction, and 13 ​% of rectum were LNM+. The study had 14,339 males (51.97 ​%). Mean age was 64.9 (±11.7). In multivariate analysis, sample was adjusted by excluding confounding factors, isolating impact of tumor size on LNM. Analysis for only tumor size, patients with colon tumors >45 ​mm had 53 ​% increased odds of LNM (95 ​% CI [1.06, 2.23], p ​= ​0.03), whereas tumor size did not significantly affect LNM in rectosigmoid and rectum cases, with odds ratios of 2.05 (95 ​% CI [0.82, 5.09], p ​= ​0.12) and 1.62 (95 ​% CI [0.97, 2.71], p ​= ​0.065) respectively, for tumors ≥45 ​mm compared to those <15 ​mm.

This investigation refines predictors of LNM, crucial for tailoring organ-sparing strategies in early-stage CRC management. While tumor size is significant determinant of LNM in colon cancer, early rectal and rectosigmoid cancers may be associated with lower risk of LNM.

Neuroblastoma (NB) is an immunologically "cold" tumor with poor or no inflamed substrates as most of solid pediatric tumors (SPT). Consistent data indicate that NB tumor microenvironment (TME) is dominated by myeloid cells, with little (but variable) T cell infiltration. The obstacles to lymphocyte infiltration and to their anti-tumor activity are due to different tumor immune evasion strategies, including loss of HLA Class I molecules, high expression of immune checkpoint molecular ligands leading to exhaustion of T effector (and NK) cells, induction of T regulatory, myeloid and stromal cells and secretion of immunosuppressive mediators. In odds with adult solid tumors, NB displays weak immunogenicity caused by intrinsic low mutational burden and scant expression of neoepitopes in the context of MHC-class I antigens which, in turn, are particularly poorly expressed on NB cells, thus inducing low anti-tumor T cell responses. In addition, NB is generated from embryonal cells and is the result of transcriptional abnormalities and not of the accumulation of genetic mutations over time, thus further explaining the low immunogenicity. The poor expression of immunogenic molecules on tumor cells is associated with the high production of immunosuppressive factors which further downregulate lymphocyte infiltration and activity, thus explaining the limited efficacy of new drugs in NB, as immune checkpoint inhibitors. This review is focused on examining the role of T effector and regulatory cells infiltrating TME of NB, taking into account their repertoire, phenotype, function, plasticity and, importantly, predictive value for defining novel targets for therapy.

In the tumor microenvironment (TME), hypoxia stands as a significant factor that modulates immune responses, especially those driven by T cells. As T cell-based therapies often fail to work in solid tumors, this study aims to investigate the effects of hypoxia on T cell topo-distribution in the TME, gene expression association with T cell states, and clinical responses in melanoma.

To generate detailed information on tumor oxygenation and T cell accessibility, we used mathematical modeling of human melanoma tissue microarrays that incorporate oxygen supply from vessels, intratumoral diffusion, and cellular uptake. We created tumor maps and derived plots showing the fraction of CD4 and CD8 T cells against the distance to the nearest vessel and oxygen pressure. To assess their function and transcriptional changes caused by hypoxia, effector T cells were generated and cultured under hypoxia (0.5% oxygen) or normoxia (21% oxygen). The T cell hypoxia-transcriptional signature was compared against datasets from msigDB, iATLAS (clinical trials of melanoma patients treated with immune checkpoint inhibitors (ICIs)), ORIEN AVATAR (real-world melanoma patients treated with ICIs), and a single-cell atlas of tumor-infiltrating lymphocytes.

We made three specific observations: (1) in melanoma T cells preferentially accumulated in oxygenated areas close to blood vessels (50-100 µm from the vasculature in the regions of high oxygen availability) but not in hypoxic areas far from blood vessels. (2) Our analysis confirmed that under hypoxia, T cell functions were significantly reduced compared with normoxic conditions and accompanied by a unique gene signature. Furthermore, this hypoxic gene signature was prevalent in resting and non-activated T cells. Notably and clinically relevant, the hypoxic T cell gene set was found to correlate with reduced overall survival and reduced progression-free survival in melanoma patients, which was more pronounced in non-responder patients undergoing ICI therapy. (3) Finally, compared with a single-cell atlas of tumor-infiltrating T cells, our hypoxia signature aligned with a population of cells at a state termed stress response state (TSTR).

Our study highlights the critical role of hypoxia in shaping T cell distribution and its correlation with clinical outcomes in melanoma. We revealed a preferential accumulation of T cells in oxygenated areas. Moreover, hypoxic T cells develop a distinct hypoxic gene signature prevalent in resting, non-activated T cells and TSTR that was also associated with poorer outcomes, particularly pronounced among non-responders to ICIs.