Abstract
Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME.
Highlights
Colorectal cancer (CRC) is one of the most common and deadliest cancers worldwide [1, 2]
Metastatic CRC remains one of the most aggressive and lethal cancers, with the large majority of patients being refractory to therapy
Disease aggressiveness and resistance to therapy has been linked to the tumor genetic makeup and a highly immunosuppressive tumor microenvironment (TME)
Summary
Colorectal cancer (CRC) is one of the most common and deadliest cancers worldwide [1, 2]. The presence of an immunosuppressive TME induces DC-mediated tolerance rather than immunity, contributing to immune escape and dampening of anti-tumor T cell responses In different studies, these effects on DCs have translated into accelerated tumor progression, increased tumor-draining lymph node metastasis, immunotherapy failure, systemic dysfunctional immune status, and poor prognosis [102, 116, 120, 143,144,145,146]. Tolerogenic and/or dysfunctional DCs, characterized by the expression of TGF-b, IL-10, IDO-1, PGE2, and PD-L1, can inhibit T cell anti-tumor responses 3 They can differentiate into and favor the expansion of immunosuppressive populations such as myeloid-derived suppressor cells (MDSCs), BDCA1+CD14+ cells, and tumor-associated macrophages (TAMs). In general and in relation to disease progression, a decreased
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