Immune mediators as potential diagnostic tools for colorectal cancer: from experimental rationale to early clinical evidence

Abstract

At the tumor site, solid tumors recruit native and adaptive infiltrating cell subtypes with a unique pattern, varying according to the organ of origin and the stage of the disease, which contributes to the complexity of the cancer microenvironment. The recruitment and activation of immune cells depend on a plethora of soluble immune mediators, including cytokines and chemokines that have a critical role in the process of cancer onset and progression. In colorectal cancer, measurement of soluble immune mediators in the serum seems to reflect the specific inflammatory reaction at the tumor site, and thus they might serve in clinical practice to improve available colorectal cancer detection and screening strategies. Clinical translation of data from experimental models could lead to the earlier detection of colorectal cancer resulting in a decreased burden of metastatic disease. These models and the most promising candidates for immune-based serum screening tests in colorectal cancer are discussed here.

Keywords::

• chemokines
• colorectal cancer
• cytokines
• diagnostic test
• immune-based serum tests
• immunity
• inflammation
• proinflammatory mediators
• screening

Acknowledgements

The authors are grateful to N Cortese for her precious comments to improve the manuscript.

Financial & competing interests disclosure

This work was supported by the Italian Association for Cancer Research (AIRC) Italy (grant number MFAG-11677 to Federica Marchesi) and the Italian Ministry of University and Research, FIRB grant (RBAP11H2R9). G Di Caro is supported by a fellowship from Fondazione Umberto Veronesi. MR Galdiero was supported by a fellowship from P.O.R. Campania FSE 2007–2013, Project crème. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Innate immune cells are main components of the tumor microenvironment and critically contribute to the onset and progression of colorectal cancer (CRC).

• Adaptive immune cells are endowed with anti-tumor activity, which is importantly regulated by the presence of tumor-associated macrophage and tumor-associated neutrophil in the tumor milieu.

• Tumor-associated macrophage and tumor-associated neutrophil modify their phenotypic and functional aspects based on the signals derived from the microenvironment.

• A plethora of soluble mediators of inflammation (cytokines and chemokines) are involved in the recruitment of innate and adaptive immune cells to the tumor microenvironment and have been shown to play a fundamental role in tumor progression from its earlier steps.

• An earlier detection would decrease the rate of metastatic CRC at diagnosis. Colonoscopy is used for this purpose, but it is an invasive and painful procedure, costly, time consuming and thus with a low compliance. Fecal occult blood test is the only non-invasive screening strategy available in CRC, it is a methodology with a high compliance but not sufficiently specific and sensitive in detecting CRC occurrence. Thus, novel immune serum tests are greatly required in CRC population screening.

• Prospective trials available suggest C-reactive protein (CRP) as an unreliable diagnostic biomarker for CRC screening. Unspecific systemic inflammatory markers such as levels of CRP, NLR and lymphocytic count are not reliably associated with the number of cells in the tumor milieu and are unlikely to reflect the inflammatory status of the CRC microenvironment. Serum levels of immune mediators are likely to efficiently reflect the specific local immune reaction in the tumor milieu compared with CRP.

• Several translational studies suggest that arrays of chemokines and cytokines in the serum might be implemented to clinical practice as novel screening markers to provide an earlier detection of CRC.

• Arrays of circulating levels of chemokines and cytokines need to be tested in properly designed prospective clinical trials with the aim to identify immune serum-based screening tests with potential diagnostic value, which might be implemented in clinical practice to improve the compliance of colonoscopy and reduce the burden of metastatic CRC at diagnosis.