Mini-reviewMicroenvironmental interactions in classical Hodgkin lymphoma and their role in promoting tumor growth, immune escape and drug resistance
Section snippets
General background
Hodgkin Lymphoma (HL) first involves lymph nodes [1]. It is characterized by a minority of tumor cells (less than 1% of the total cell population), collectively termed Hodgkin and Reed–Sternberg (HRS) cells, representing the small, mono-nucleated Hodgkin (H) cells and the large, binucleated or multi-nucleated Reed–Sternberg (RS) cells [2], [3] embedded in an inflammatory microenvironment.
HL has been divided into classical HL (cHL), which accounts for 95% of all cases, and the less frequent
cHL microenvironment composition
HRS cells represent about 1% of the tumor mass, but through efficient organization of the abundant surrounding immune cells, they are able to generate a highly aggressive and potentially lethal malignancy. The cHL microenvironment is composed by numerous small CD4-positive T cells and a variable number of eosinophils, histiocytes/macrophages, B-cells, mast cells, plasma cells, fibroblasts, mesenchymal stromal cells (MSCs) and endothelial cells (Fig. 1). HRS cells are often in close contact with
The Tumor-Hosts symbiosis in cHL microenvironment
The lack of the B-cell receptor (BcR) makes the low number of HRS cells susceptible to apoptosis, forcing them to survive by building a friendly/protective microenvironment unable to exert an effective immune response (Fig. 1, Fig. 2).
HRS cells apply several strategies to create their TME: i) recruitment (direct) of immune cells by cytokines/chemokines secreted by HRS cells or normal cells “educated” by tumor cells [33], [34] (Fig. 1); ii) modification of immune cells' phenotype (Fig. 2); iii)
Immune escape mechanisms
HRS cells have developed efficient immunosuppressive mechanisms to proliferate and survive for long periods. They live surrounded by immune cells “educated” to build an immune privileged niche that, instead of exerting anti-tumor effects, promotes the growth/survival of HRS cells. As a consequence, the activity, type, number and proportions of TME cells are now considered new prognostic factors as well as targets for new therapeutic approaches [60].
HRS cells employ different mechanisms to
Autocrine and TME-mediated proliferation and survival of HRS cells
Several pro-survival/proliferative signals determine the fate of HRS cells. The current hypothesis is that HRS cells can grow through the expression of cytokines and tyrosine kinase receptors (RTKs) and their corresponding ligands (autocrine mechanisms) or through the continuous stimulation by the extracellular matrix and by molecules secreted and/or surface expressed by TME cells (paracrine mechanisms). Also the constitutive activation of the NF-kB pathway in HRS cells may be due to autocrine
The impact of TME on drug response
Emerging data suggest that TME, by providing a protective niche, allows cancer cells to escape from the cytotoxic effects of chemotherapy and radiation [96], [97]. Indeed, drugs very active in vitro do not always get good results in vivo. An example is the proteasome inhibitor Bortezomib that exerted a potent anticancer activity in vitro against HRS cells but not in vivo when used as a single drug [98].
Given the role of TME in cHL, it is fundamental to discover what are the microenvironmental
Conclusion
Based on current knowledge, it is clear that HRS cells in symbiosis with “normal cells” build a tumor microenvironment where apparently all goes well: tumor grows if the TME grows; the TME grows if tumor cells survive; tumor cells survive if TME counteracts the cytotoxic effects of anticancer therapies and immunity.
However, there are a lot of open questions. For example, the role of immunosuppressive cells such as Tregs or M2-immunosuppressive monocytes is not so clear. Indeed, several authors
Conflict of interest
The authors have no competing interests.
Acknowledgments
The authors apologize to researchers whose work is not cited due to space limitations.
This work was supported by a grant from the Italian Association for Cancer Research (AIRC; grant no. IG 15844 to DA) and by Ministero della Salute, Ricerca Finalizzata FSN, I.R.C.C.S., Rome, Italy.
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