Tumor secretome shapes the immune landscape during cancer progression

Abstract

The focus of cancer immunotherapy has traditionally been on immune cells and tumor cells themselves, often overlooking the tumor secretome. This review provides a comprehensive overview of the intricate relationship between tumor cells and the immune response in cancer progression. It highlights the pivotal role of the tumor secretome - a diverse set of molecules secreted by tumor cells - in significantly influencing immune modulation, promoting immunosuppression, and facilitating tumor survival. In addition to elucidating these complex interactions, this review discusses current clinical trials targeting the tumor secretome and highlights their potential to advance personalized medicine strategies. These trials aim to overcome the challenges of the tumor microenvironment by designing therapies tailored to the secretome profiles of individual cancer patients. In addition, advances in proteomic techniques are highlighted as essential tools for unraveling the complexity of the tumor secretome, paving the way for improved cancer treatment outcomes.

Keywords: Biomarkers; Immunotherapy; Tumor microenvironment; Tumor secretome; Tumor-immune cell interplay.

Fig. 1

Impact of the tumor secretome on cancer development and progression. Components secreted by tumor cells play a critical role in the process of pre-metastasis and metastasis via the blood and lymphatic systems. In addition, such secreted substances often enter the blood or lymphatic system earlier than tumor cells to reach the secondary metastatic site

Fig. 2

Crosstalk between tumor cells and immune cells. Tumor cells secrete various factors to recruit and activate or inactivate immune cells such as CD8⁺ T cells, CD4⁺ T cells, monocytes, and NK cells. Meanwhile, various immune cells also secrete specific factors to inactivate or inhibit the function of immune cells. This regulation governs the maintenance of the tumor niche, tumor development, and tumor immune function

Fig. 3

Overview of the main methods for detecting tumor secretome in research. (A) ELISA. Fluids are collected and placed on ELISA plates that have been pre-coated with a specific capture antibody. The target protein adheres to this antibody, and then an enzyme-linked detection antibody is introduced. The protein’s concentration is determined by measuring the colorimetric shift that occurs when the enzyme reacts with its substrate. (B) Antibody arrays. Samples containing secreted proteins from cell culture or body fluids are incubated with precoated antibody arrays. Specific antibodies immobilized on the array capture various secreted proteins. Bound proteins are detected using a reporter molecule conjugated to a secondary antibody, allowing simultaneous quantification of multiple proteins in a single sample and providing a comprehensive secretome profile. (C) Mass spectrometry after immunoprecipitation. After collection and concentration of cell culture supernatants or body fluids, secretome immunoprecipitation is performed. Biomolecules of interest are isolated and analyzed by mass spectrometry to identify and quantify secreted proteins and metabolites. (D) ER-BioID^HA biotinylation technique. The ER-BioID^HA plasmid is transfected into tumor cells to enable biotinylation of secreted proteins. Biotin is added to the culture and secreted proteins are biotinylated in situ. Streptavidin-based immunoprecipitation is performed to isolate the biotinylated proteins, which are then analyzed by mass spectrometry to identify a specific set of secreted molecules

Fig. 4

Overview of the bench-to-bedside and bedside-to-bench approaches for personalized treatment and patient management through tumor secretome analysis. The secretome profiles of individual patient tumors are analyzed to identify unique molecular signatures. In the laboratory, these tumors are subjected to thorough screening for potential drug candidates, taking into account their inherent heterogeneity, dynamic metabolic profiles, and specific protein expression patterns. Drug sensitivity assays are performed to optimize therapeutic efficacy and assess patient response. Clinically, treatment recommendations are based on laboratory findings, allowing for personalized therapy adjustments. Treatment efficacy is carefully monitored and the risk of relapse is assessed. Large patient cohorts are monitored and extensive clinical follow-up is performed, using advanced data analytics to refine treatment strategies and improve outcomes