Metastasis is the leading cause of cancer-related deaths and despite measurable progress in the field, underlying mechanisms are still not fully understood. Circulating tumor cells (CTCs) disseminate within the bloodstream, where most of them die due to the attack of the immune system. On the other hand, recent evidence shows active interactions between CTCs and platelets, myeloid cells, macrophages, neutrophils, and other hematopoietic cells that secrete immunosuppressive cytokines, which aid CTCs to evade the immune system and enable metastasis. Platelets, for instance, regulate inflammation, recruit neutrophils, and cause fibrin clots, which may protect CTCs from the attack of Natural Killer cells or macrophages and facilitate extravasation. Recently, a correlation between the commensal microbiota and the inflammatory/immune tone of the organism has been stablished. Thus, the microbiota may affect the development of cancer-promoting conditions. Furthermore, CTCs may suffer phenotypic changes, as those caused by the epithelial–mesenchymal transition, that also contribute to the immune escape and resistance to immunotherapy. In this review, we discuss the findings regarding the collaborative biological events among CTCs, immune cells, and microbiome associated to immune escape and metastatic progression.

Background Immune-checkpoint inhibitors (ICIs) changed the therapeutic landscape of patients with lung cancer. However, only a subset of them derived clinical benefit and evidenced the need to identify reliable predictive biomarkers. Liquid biopsy is the non-invasive and repeatable analysis of biological material in body fluids and a promising tool for cancer biomarkers discovery. In particular, there is growing evidence that extracellular vesicles (EVs) play an important role in tumor progression and in tumor-immune interactions. Thus, we evaluated whether extracellular vesicle PD-L1 expression could be used as a biomarker for prediction of durable treatment response and survival in patients with non-small cell lung cancer (NSCLC) undergoing treatment with ICIs. Methods Dynamic changes in EV PD-L1 were analyzed in plasma samples collected before and at 9 ± 1 weeks during treatment in a retrospective and a prospective independent cohorts of 33 and 39 patients, respectively. Results As a result, an increase in EV PD-L1 was observed in non-responders in comparison to responders and was an independent biomarker for shorter progression-free survival and overall survival. To the contrary, tissue PD-L1 expression, the commonly used biomarker, was not predictive neither for durable response nor survival. Conclusion These findings indicate that EV PD-L1 dynamics could be used to stratify patients with advanced NSCLC who would experience durable benefit from ICIs.

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