Efficacy and safety of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy in patients with pancreatic cancer peritoneal metastasis.

OBJECTIVES: Pancreatic cancer with peritoneal metastasis presents a challenging prognosis, with limited effective treatment options available. This study aims to evaluate the efficacy and safety of combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as a treatment strategy for this patient group. METHODS: A retrospective analysis was conducted on patients with peritoneal metastasis of pancreatic cancer who underwent CRS + HIPEC treatment at Beijing Shijitan Hospital from March 2017 to December 2023. The study focused on assessing clinical features, the incidence of sever adverse events (SAEs), and overall survival (OS). RESULTS: A total of 10 patients were enrolled in this study. The median OS was 24.2 months, suggesting an improvement over traditional therapies. While SAEs were noted, including two cases of severe complications necessitating additional surgical interventions, no perioperative fatalities were recorded. The overall survival time for patients with CC0/1 was not significantly different from that of patients with CC2/3, and no prognostic predictors were identified. CONCLUSIONS: The combination of CRS and HIPEC appears to be a viable and promising treatment modality for patients with peritoneal metastasis of pancreatic cancer, offering an improved survival rate with manageable safety concerns. Further research is needed to refine patient selection criteria and to explore the long-term benefits of this approach.

Bilateral breast metastases from anaplastic lymphoma kinase-positive lung cancer in a male: a case report.

BACKGROUND: Distant metastases from lung cancer are commonly found in the brain, bone, and liver. Metastases to the breast from non-mammary malignancies are extremely rare, and their clinical presentations remain unclear. CASE PRESENTATION: We herein report a case of bilateral breast metastases from anaplastic lymphoma kinase-positive advanced lung cancer in a 51-year-old Japanese male patient. During the course of systemic treatment for advanced lung cancer, computed tomography revealed bilateral breast enlargement without contrast enhancement, a finding consistent with gynecomastia. While other metastatic lesions responded to chemotherapy, both breast masses grew vertically like nodules. The breast masses were immunohistochemically diagnosed as metastases from lung cancer and were removed surgically. Simultaneous bilateral breast metastases from malignancies of other organs, like ones in this case, have rarely been described. CONCLUSIONS: It is important to keep in mind that breast metastases from nonmammary malignancies are a possible explanation for unusual breast findings in a patient with a history of malignancies.

The challenge of molecular selection in liver-limited metastatic colorectal cancer for surgical resection: a systematic review and meta-analysis in the context of current and future approaches.

Objectives: Treatment of metastatic colorectal cancer (mCRC) includes resection of liver metastases (LM), however, no validated biomarker identifies patients most likely to benefit from this procedure. This meta-analysis aimed to assess the impact of the most relevant molecular alterations in cancer-related genes of CRC (i.e., RAS, BRAF, SMAD4, PIK3CA) as prognostic markers of survival and disease recurrence in patients with mCRC surgically treated by LM resection. Methods: A systematic literature review was performed to identify studies reporting data regarding survival and/or recurrence in patients that underwent complete liver resection for CRC LM, stratified according to RAS, BRAF, PIK3CA, and SMAD4 mutational status. Hazard ratios (HRs) from multivariate analyses were pooled in the meta-analysis and various adjustment strategies for confounding factors were combined. The search was conducted in numerous databases, including MEDLINE (PubMed), Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO host), and WHO Global Index Medicus, through March 18th, 2022. Meta-analyses, editorials, letters to the editor, case reports, studies on other primary cancers, studies with primary metastatic sites other than the liver, studies lacking specific oncological outcome variables or genetic data, non-English language studies, and studies omitting residual disease data from liver metastasectomy were excluded. The remaining 47 studies were summarized in a descriptive table which outlines the key characteristics of each study and final results were graphically presented. Results: RAS mutation status was negatively associated with overall survival (OS) (HR, 1.68; 95% CI, 1.54-1.84) and recurrence free survival (RFS) (HR, 1.46; 95% CI, 1.33-1.61). A negative association was also found for BRAF regarding OS (HR, 2.64; 95% CI, 2.15-3.24) and RFS (HR, 1.89; 95% CI, 1.32-2.73) and SMAD4 regarding OS (HR, 1.93; 95% CI, 1.56-2.38) and RFS (HR, 1.95; 95% CI, 1.31-2.91). For PIK3CA only three studies were eligible and no significant association with either OS or RFS could be highlighted. Conclusion: RAS, BRAF, and SMAD4 are negatively associated with OS and RFS in patients undergoing curative liver metastasectomy from colorectal cancer. No conclusion can be drawn for PIK3CA due to the limited literature availability. These data support the integration of RAS, BRAF, and SMAD4 mutational status in the surgical decision-making for colorectal liver metastasis. Nevertheless, we have to consider several limitations, the major ones being the pooling of results from studies that evaluated patient outcomes as either disease-free survival (DFS) or RFS; the inclusion of patients with minimal residual disease and unconsidered potential confounding factors, such as variability in resectability definitions, chemotherapy use, and a potential interaction between biological markers and pre- and post-resection pharmacological treatments.

The #HOPE4LIVER Single-Arm Pivotal Trial for Histotripsy of Primary and Metastatic Liver Tumors.

Background Histotripsy is a nonthermal, nonionizing, noninvasive, focused US technique that relies on cavitation for mechanical tissue breakdown at the focal point. Preclinical data have shown its safety and technical success in the ablation of liver tumors. Purpose To evaluate the safety and technical success of histotripsy in destroying primary or metastatic liver tumors. Materials and Methods The parallel United States and European Union and England #HOPE4LIVER trials were prospective, multicenter, single-arm studies. Eligible patients were recruited at 14 sites in Europe and the United States from January 2021 to July 2022. Up to three tumors smaller than 3 cm in size could be treated. CT or MRI and clinic visits were performed at 1 week or less preprocedure, at index-procedure, 36 hours or less postprocedure, and 30 days postprocedure. There were co-primary end points of technical success of tumor treatment and absence of procedure-related major complications within 30 days, with performance goals of greater than 70% and less than 25%, respectively. A two-sided 95% Wilson score CI was derived for each end point. Results Forty-four participants (21 from the United States, 23 from the European Union or England; 22 female participants, 22 male participants; mean age, 64 years ± 12 [SD]) with 49 tumors were enrolled and treated. Eighteen participants (41%) had hepatocellular carcinoma and 26 (59%) had non-hepatocellular carcinoma liver metastases. The maximum pretreatment tumor diameter was 1.5 cm ± 0.6 and the maximum post-histotripsy treatment zone diameter was 3.6 cm ± 1.4. Technical success was observed in 42 of 44 treated tumors (95%; 95% CI: 84, 100) and procedure-related major complications were reported in three of 44 participants (7%; 95% CI: 2, 18), both meeting the performance goal. Conclusion The #HOPE4LIVER trials met the co-primary end-point performance goals for technical success and the absence of procedure-related major complications, supporting early clinical adoption. Clinical trial registration nos. NCT04572633, NCT04573881 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Nezami and Georgiades in this issue.

68Ga-DOTATATE PET/CT Imaging of a Solitary Nasopharyngeal Metastasis of Merkel Cell Carcinoma.

ABSTRACT: Merkel cell carcinoma (MCC) is an uncommon highly aggressive cutaneous neuroendocrine neoplasm with high mortality. Rarer still is nasopharyngeal metastasis of MCC. Herein, we report the 68Ga-DOTATATE PET/CT findings of MCC with metastasis to the nasopharynx in a 53-year-old man who underwent surgery for MCC in his thigh 2 years ago.

Risk factors and impact of occult and skip metastasis in early-stage oral tongue squamous cell carcinoma.

OBJECTIVES: To investigate risk factors associated with occult lymph node metastases (ONM) and skip metastasis in early-stage oral tongue squamous cell carcinoma (OTSCC) patients. Meanwhile, to analyze the contribution of metastatic nodes to survival outcomes. MATERIALS AND METHODS: 544 OTSCC patients who were clinically staged T1-T2N0 with pathologic results from May 2018 to January 2024 were enrolled. Those with ONM were divided into subgroups with or without skip metastasis. Clinical, laboratorial, radiological and pathological factors between groups were analyzed by using univariate analysis and multivariate logistic analysis. The association of tumor growth behavior with the metastatic pattern of lymph nodes was summarized. Additionally, disease free survival (DFS) among different groups were compared using Kaplan-Meier analysis. RESULTS: Tumor growth behavior was associated with ONM. Tumor thickness with a threshold of 6.4 mm was not inferior to histological depth of invasion in predicting ONM. Only 1.3% of patients had nodal involvement of neck level IV or V. The DFS of patients with ONM were significantly reduced than those without ONM (P < 0.001). The DFS between patients with and without skip metastasis exhibited no statistical significance(P = 0.246). The 1-year, 2-year recurrence rates of patients with or without ONM were 31.9%, 37.5%, 10.1% and 14.0%, correspondingly. CONCLUSIONS: Tumor thickness with a threshold of 6.4 mm could be used as a preoperative predictor for ONM. Elective neck dissection of level I - III might be sufficient for early stage OTSCC patients. OTSCC patients with ONM should be closely observed during the first 2 years after surgery. CLINICAL RELEVANCE: The risk of ONM in early stage OTSCC patients might be predicted by tumor thickness calculated on MR imaging. Elective neck dissection of level I - III could remove micrometastases timely and effectively.

Indications for nuclear medicine imaging in prostate cancer.

Nuclear medicine imaging for prostate cancer has advanced significantly over the past decade. A survey is presented in this review. PSMA-PET/CT is a new highly accurate method that has been introduced, but bone scans and bone-PET continue to be widely applied. PSMA-PET/CT still lacks sufficient patient outcome data to be recommended for treatment allocation when used for primary staging. However, the literature and clinical guidelines support its use at the stage of biochemical recurrence. In Denmark, the use of nuclear medicine examinations for prostate cancer aligns with clinical guideline recommendations.

Identification of Biomarkers Associated With Paget's Disease of Bone and Bone Metastasis From Breast Cancer Patients.

BACKGROUND: The bone is among the most frequently chosen sites for the metastatic spread of breast cancer. The prediction of biomarkers for BM (Bone Metastasis) and PDB (Paget's disease of bone) initiated from breast cancer could be critically important in categorizing individuals with a higher risk and providing targeted treatment for PDB and BM. AIMS: This research aims to investigate the common key candidate biomarkers that contribute to BM-BCa (Bone metastasis of breast cancer) and PDB by employing network decomposition and functional enrichment studies. METHODS AND RESULTS: This research analyzed high-throughput transcriptome sequencing (RNA-Seq). For this work, the dataset (GSE121677) was downloaded from GEO (Gene Expression Omnibus), and DEGs were identified using Galaxy and R script 4.3. Using STRING (Search Tool for the Retrieval of Interacting Genes), high-throughput research created a protein-protein interaction network (PPIN). The BM-PDB-interactome was created using Cytoscape 3.9.1 and PDB biomarkers, with the top 3% DEGs from BM-BCa. Functional Enrichment Analysis (Funrich 3.1.3) and DAVID 6.8 performed functional and gene set enrichment analysis (GSEA) of putatively essential biomarkers. TCGA (The Cancer Genome Atlas) validated the discovered genes. Based on our research, we identified 1262 DEGs; among these DEGs, 431 genes were upregulated, and 831 genes were downregulated. During the third growth of the interactome, 20 more genes were pinned to the BM-PDB interactome. RAC2, PIAS1, EP300, EIF2S1, and LRP6 are among the additional 25% of genes identified to interact with the BM-PDB interactome. To corroborate the findings of the research presented, additional functional and gene set enrichment analyses have been performed. CONCLUSION: Of the five reported genes (RAC2, PIAS1, EP300, EIF2S1, and LRP6), RAC2 was identified to function as the common key potential biomarker in the BM-PDB interactome analysis and validated by TCGA in the study presented.

Increasing monocytes after lung cancer surgery triggers the outgrowth of distant metastases, causing recurrence.

Patients with lung cancer have a high incidence of tumor recurrence even after curative surgical resection. Some reports indicated that immunosuppressive cells induced by surgical stress could contribute to tumor recurrence after surgery; however, the underlying mechanisms are not fully understood. In this study, we found that increased postoperative blood monocytes served as a risk factor for tumor recurrence in 192 patients with non-small cell lung cancer (NSCLC). We established the lung cancer recurrent mouse model after tumor resection and showed that the surgical stress immediately increased the level of serum monocyte chemoattractant protein-1 (MCP-1), which subsequently increased blood monocytes. These blood monocytes were rapidly recruited into distant micrometastases and became tumor growth-promoting tumor associated macrophages (TAMs). Furthermore, even after the blood MCP-1 and monocytes decreased enough 72 h after tumor resection, TAMs in micrometastases remained rich because the MCP-1 secreted by micrometastases themselves continued to recruit monocytes around the tumor. Consequently, tumor resection triggered the outgrowth of distant metastases via the MCP-1-Monocyte-TAM axis. When we administered the MCP-1 inhibitor to the lung cancer recurrent model mice, blood monocytes decreased after tumor resection, and TAMs in micrometastases also dramatically decreased. Finally, peri- and postoperative treatment with the MCP-1 inhibitor suppressed distant metastases after surgery. Targeting the MCP-1-Monocyte-TAM axis may inhibit surgical stress-induced NSCLC recurrence by attenuating postoperative immunosuppressive monocytes in micrometastases.

Complex mechanism of brugada phenocopy: moderate hyponatremia and right ventricular compression by liver metastatic tumor - case report.

Brugada phenocopy (BrP) occurs in various clinical conditions and manifests as a Brugada-like ECG pattern with coved (type 1) or saddle-back (type 2) ST-segment elevation in the right precordial leads. Unlike Brugada syndrome (BrS), which is an inherited channelopathy, BrP is not associated with an increased risk of malignant arrhythmia. BrP has been reported in severe metabolic disturbances (significant hyponatremia, hypokalemia or hyperkalemia), mechanical heart compression, coronary artery disease, pulmonary embolism and myocarditis/pericarditis. The authors described a case of a 69-year-old female whose Brugada-like ECG was atypically associated with only moderate hyponatremia (127 mmol/l). She was admitted due to a skin and subcutaneous tissue infection of the left shank and coexistent urinary tract infection (without a fever). She had the history of advanced melanoma with multiple liver metastases. Her cardiac history was negative, especially the patient has never suffered from ventricular arrhythmias. ECG on admission showed saddle-back ST-segment elevation in the right precordial leads; however, the patient did not report any chest pain. Troponin I level and left ventricular function in echocardiography were normal while regional longitudinal strain in RV apex was decreased and showed post-systolic shortening. The substernal view revealed compression of the right ventricle (RV) by liver metastatic tumor. ECG changes disappeared quickly during natrium chloride supplementation and did not recur during hospitalization. This case illustrates that even moderate hyponatremia may be a reversible cause of BrP when other predisposing conditions (e.g. heart compression by tumor) coexist.

Post nephrectomy metachronous testicular metastasis in a case of clear cell renal cell carcinoma (ccRCC).

It is highly uncommon for solid tumours to metastasise to the testis. Here, we report a case of metachronous testicular metastasis from clear cell renal cell cancer (RCC) in a male patient 3 years after left radical nephrectomy. Ultrasound of the scrotum showed a 3.5 cm × 4 cm left testicular mass with normal serum tumour markers. The patient underwent left high inguinal orchidectomy, which revealed metastatic renal cell carcinoma. CT of the chest, abdomen and pelvis showed multiple liver secondaries. Cabozantinib was started for metastatic RCC, and the patient showed no evidence of disease progression in a follow-up of 1 year.

FOSL1 promotes stem cell­like characteristics and anoikis resistance to facilitate tumorigenesis and metastasis in osteosarcoma by targeting SOX2.

Metastasis is the leading cause of cancer­related death in osteosarcoma (OS). OS stem cells (OSCs) and anoikis resistance are considered to be essential for tumor metastasis formation. However, the underlying mechanisms involved in the maintenance of a stem­cell phenotype and anoikis resistance in OS are mostly unknown. Fos­like antigen 1 (FOSL1) is important in maintaining a stem­like phenotype in various cancers; however, its role in OSCs and anoikis resistance remains unclear. In the present study, the dynamic expression patterns of FOSL1 were investigated during the acquisition of cancer stem­like properties using RNA sequencing, PCR, western blotting and immunofluorescence. Flow cytometry, tumor­sphere formation, clone formation assays, anoikis assays, western blotting and in vivo xenograft and metastasis models were used to further investigate the responses of the stem­cell phenotype and anoikis resistance to FOSL1 overexpression or silencing in OS cell lines. The underlying molecular mechanisms were evaluated, focusing on whether SOX2 is crucially involved in FOSL1­mediated stemness and anoikis in OS. FOSL1 expression was observed to be upregulated in OSCs and promoted tumor­sphere formation, clone formation and tumorigenesis in OS cells. FOSL1 expression correlated positively with the expression of stemness­related factors (SOX2, NANOG, CD117 and Stro1). Moreover, FOSL1 facilitated OS cell anoikis resistance and promoted metastases by regulating the expression of apoptosis related proteins BCL2 and BAX. Mechanistically, FOSL1 upregulated SOX2 expression by interacting with the SOX2 promoter and activating its transcription. The results also showed that SOX2 is critical for FOSL1­mediated stem­like properties and anoikis resistance. The current findings indicated that FOSL1 is an important regulator that promotes a stem cell­like phenotype and anoikis resistance to facilitate tumorigenesis and metastasis in OS by regulating the transcription of SOX2. Thus, FOSL1 might represent an attractive target for therapeutic interventions in OS.

Dynamic changes in immune cells in humanized liver metastasis and subcutaneous xenograft mouse models.

Preclinical drug efficacy and tumor microenvironment (TME) investigations often utilize humanized xenograft mouse models, yet these models typically fall short in replicating the intricate TME. We developed a humanized liver metastasis (LM) model by transplanting human peripheral blood mononuclear cells (PBMCs) and assessed it against the conventional subcutaneous (SC) xenograft model, focusing on immune cell dynamics post-transplantation and immunotherapy response. NOD-scid IL2Rgammanull(NSG) were inoculated with PBMCs to create humanized models. We induced SC and LM models using HCT116 cells, to investigate and compare the distributions and transformations of immune cell subsets, respectively. Both models were subjected to anti-PD-L1 therapy, followed by an analysis the TME analysis. The LM model demonstrated enhanced central tumor infiltration by tumor-infiltrating lymphocytes (TILs) compared to the peripheral pattern of SC model. TIL subpopulations in the LM model showed a progressive increase, contrasting with an initial rise and subsequent decline in the SC model. Post-anti-PD-L1 therapy, the LM model exhibited a significant rise in central and effector memory T cells, a response absents in the SC model. Our study highlights differential TME responses between SC and LM models and introduces a robust humanized LM model that swiftly indicates the potential efficacy of immunotherapies. These insights could streamline the preclinical evaluation of TME-targeting immunotherapeutic agents.

Mapping the transcriptional evolution of human metastatic breast cancer.

Many aspects of breast cancer metastasis remain poorly understood, despite its clinical importance. In this issue of the JCI, Winkler et al. have applied an elegant patient-derived xenograft (PDX) model to map the transcriptomes of single cells in matched primary tumors and lung metastases across 13 breast cancer PDX models. They identified distinct transcriptional changes associated with metastatic evolution in lowly and highly metastatic primary tumors. Furthermore, by classifying the "epithelial-mesenchymal plasticity" (EMP) state of single cells, they revealed that considerable EMP heterogeneity exists among primary and metastatic human breast cancer cells. However, the EMP profile of a tumor does not change substantially upon metastasis. These findings give an unprecedentedly detailed view into the transcriptional heterogeneity and evolution of metastatic human breast cancer.

[Proteomic analysis of differentially expressed proteins in gastrointestinal neuroendocrine tumors and their liver metastasis].

Objective: To investigate the differences of protein expressions in the primary tumors, adjacent tissues, and metastatic tumors of gastrointestinal neuroendocrine neoplasms. Methods: Nine patients with gastrointestinal neuroendocrine tumors (GI-NENs) with liver metastasis who underwent surgery at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences from July 2015 to April 2019 were selected. The protein expressions of the primary tissues, liver metastatic tissues, and adjacent tissues were detected by the data independent acquisition (DIA) technology. P<0.05 and | log2FC|>0.5 (FC as the difference multiple) were used as the criteria to identify the differentially expressed proteins in the primary tissues vs adjacent tissues, primary tissues vs liver metastatic tissues, primary tissues with different degrees of differentiation, and liver metastatic tissues with different degrees of differentiation. The differentially expressed proteins were investigated by volcano map analysis, cluster analysis, Gene Ontology (GO) function analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results: Compared with adjacent tissues, 85 proteins were downregulated and 42 proteins were upregulated in the primary tissues of gastric NENs. The differentially expressed proteins were mainly enriched in the biological processes related to the regulation of guanosidase triphosphate activity and the catabolism of deoxyribonucleoside monophosphate, the glycosaminoglycan biosynthesis chondroitin sulfate/dermatan sulfate, pantothenate, and CoA biosynthesis signaling pathways. 114 proteins were downregulated and 155 proteins were upregulated in the primary tissues of intestinal NENs. The differentially expressed proteins were mainly enriched in the biological processes related to glutathione metabolism and sulfur compound metabolism, collecting duct acid secretion, and taurine and hytaurine metabolism signaling pathways. Compared with the primary tissues of neuroendocrine cancers (NECs), 168 proteins were downregulated and 278 proteins were upregulated in G1-2 differentiation primary tissues. The differentially expressed proteins were significantly enriched in biological processes such as DNA metabolism and DNA replication, as well as replication, mismatch repair, and other pathways. Compared with the metastatic tissues of NECs, 95 proteins were downregulated and 97 proteins were upregulated in G1-2 differentiated metastases. The differentially expressed proteins were significantly enriched in the activity and catalytic activity of transcriptional coactivators, base excision repair, and protein efflux pathways. Compared with G1 differentiated primary tissues, 530 proteins were downregulated and 211 proteins were upregulated in G1 differentiated metastatic tissues. Compared with G2 differentiated primary lesions, 53 proteins were downregulated and 96 proteins were upregulated in G2 differentiated metastatic tissues. Compared with the primary lesions of NECs, 109 proteins were downregulated and 92 proteins were upregulated in the metastatic tissues of NECs. In G1 and G2 differentiated GI-NENs, there are many similar signal pathways enriched in differentially expressed proteins between primary lesions and metastases, while only one signal pathway enriched in differentially expressed proteins between primary and metastatic tissues of NECs is the same as that enriched in differentially expressed proteins between primary and metastatic tissues of GI-NENs, which is the drug metabolism signal pathway. The differentially expressed proteins in G1 differentiated primary and metastatic tissues were mainly expressed in cytoplasm (20.26%), mitochondria (18.67%), and nucleus (15.48%). The differentially expressed proteins in the primary and metastatic tissues of G2 differentiation were mainly expressed in the cytoplasm (20.24%), nucleus (18.25%), and cell membrane (15.08%). The differentially expressed proteins in the primary and metastatic tissues of NECs were mainly expressed in the nucleus (23.78%), cytoplasm (22.7%), and cell membrane (11.35%). Conclusion: The protein expressions of GI-NENs in the primary tissues, adjacent tissues, and metastatic tissues were significantly different in different sites and degrees of differentiation.

Immunotherapy revolutionizing brain metastatic cancer treatment: personalized strategies for transformative outcomes.

Brain metastatic cancer poses a significant clinical challenge, with limited treatment options and poor prognosis for patients. In recent years, immunotherapy has emerged as a promising strategy for addressing brain metastases, offering distinct advantages over conventional treatments. This review explores the evolving landscape of tumor immunotherapy in the context of brain metastatic cancer, focusing on the intricate interplay between the tumor microenvironment (TME) and immunotherapeutic approaches. By elucidating the complex interactions within the TME, including the role of immune cells, cytokines, and extracellular matrix components, this review highlights the potential of immunotherapy to reshape the treatment paradigm for brain metastases. Leveraging immune checkpoint inhibitors, cellular immunotherapies, and personalized treatment strategies, immunotherapy holds promise in overcoming the challenges posed by the blood-brain barrier and immunosuppressive microenvironment of brain metastases. Through a comprehensive analysis of current research findings and future directions, this review underscores the transformative impact of immunotherapy on the management of brain metastatic cancer, offering new insights and opportunities for personalized and precise therapeutic interventions.

CCL19-producing fibroblasts promote tertiary lymphoid structure formation enhancing anti-tumor IgG response in colorectal cancer liver metastasis.

Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS- tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG+ plasma cells (PCs), while TLS- tumors are characterized with IgA+ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19+ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM.