Colorectal cancer (CRC) remains one of the most aggressive and lethal cancers, with metastasis accounting for most deaths. As such, there is an unmet need for improved therapies for metastatic CRC (mCRC). Currently, the research focus is shifting towards the reciprocal interactions within the tumor microenvironment (TME), which prevent tumor clearance by the immune system. Dendritic cells (DCs) play a key role in the initiation and amplification of anti-tumor immune responses and in driving the clinical success of immunotherapies. Dissecting the interactions between DCs and CRC cells may open doors to identifying key mediators in tumor progression, and possible therapeutic targets. This requires representative, robust and versatile models and tools. Currently, there is a shortage of such in vitro systems to model the CRC TME and its tumor-immune cell interactions. Here we develop and establish a dynamic organotypic 3D co-culture system to recapitulate and untangle the interactions between DCs and patient-derived mCRC tumor organoids. To our knowledge, this is the first study investigating human DCs in co-culture with tumor organoids in a 3D, organotypic setting. This system reveals how mCRC organoids modulate and shape monocyte-derived DCs (MoDCs) behavior, phenotype, and function, within a collagen matrix, using techniques such as brightfield and fluorescence microscopy, flow cytometry, and fluorescence-activated cell sorting. Our 3D co-culture model shows high viability and extensive interaction between DCs and tumor organoids, and its structure resembles patient tissue sections. Furthermore, it is possible to retrieve DCs from the co-cultures and characterize their phenotypic and functional profile. In our study, the expression of activation markers in both mature and immature DCs and their ability to activate T cells were impacted by co-culture with tumor organoids. In the future, this direct co-culture platform can be adapted and exploited to study the CRC-DC interplay in more detail, enabling novel and broader insights into CRC-driven DC (dys)function.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Local treatment of metastases by surgical resection or other ablative therapies is technically feasible in an increasing number of patients with multi-organ metastatic cancer. This results in a growing debate on whether patients with extensive disease, that is traditionally deemed unresectable, may benefit from local treatment of metastases when added to standard palliative systemic therapy. For selected patients with oligometastatic colorectal cancer, local treatment of metastases has become the standard of care based on retrospective reports showing long-term survival rates. In addition to systemic therapy, preliminary evidence suggests that patients with extensive metastatic colorectal cancer may also benefit from local treatment. Here, we present the future perspectives based on the available literature on local treatment approaches in colorectal cancer.

Introduction. Local treatment of metastases is frequently performed in patients with multiorgan metastatic colorectal carcinoma (mCRC) analogous to selected patients with oligometastatic disease for whom this is standard of care. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival benefit from tumor debulking in addition to chemotherapy in patients with multiorgan mCRC. Here, we report the preplanned safety and feasibility evaluation after inclusion of the first 100 patients. Methods. Patients were eligible if at least 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy. In case of clinical benefit after three or four cycles of respectively 5-fluorouracil/leucovorin or capecitabine and oxaliplatin AE bevacizumab patients were randomized to tumor debulking followed by chemotherapy in the intervention arm, or standard treatment with chemotherapy. Results. Twelve patients dropped out prior to randomization for various reasons. Eighty-eight patients were randomized to the standard (n = 43) or intervention arm (n = 45). No patients withdrew after randomization. Debulking was performed in 82% (n = 37). Two patients had no lesions left to treat, five had progressive disease, and one patient died prior to local treatment. In 15 patients (40%) 21 serious adverse events related to debulking were reported. Postoperative mortality was 2.7% (n = 1). After debulking chemotherapy was resumed in 89% of patients. Conclusion. Tumor debulking is feasible and does not prohibit administration of palliative chemotherapy in the majority of patients with multiorgan mCRC, despite the occurrence of serious adverse events related to local treatment. The Oncologist 2020;25:e1195-e1201 Implications for Practice: This first prospective randomized trial on tumor debulking in addition to chemotherapy shows that local treatment of metastases is feasible in patients with multiorgan metastatic colorectal cancer and does not prohibit administration of palliative systemic therapy, despite the occurrence of serious adverse events related to local treatment. The trial continues accrual, and overall survival (OS) data and quality of life assessment are collected to determine whether