Cancer Letters

Cancer Letters

Volume 380, Issue 1, 28 September 2016, Pages 243-252
Cancer Letters

Mini-review
Microenvironmental interactions in classical Hodgkin lymphoma and their role in promoting tumor growth, immune escape and drug resistance

https://doi.org/10.1016/j.canlet.2015.10.007Get rights and content

Highlights

  • HRS cells build and communicate with the TME using cytokines/chemokines, angiogenic factors and extracellular vesicles.

  • The TME helps HRS cells to escape from anti-tumor responses.

  • HRS cells educate “normal cells” to create a protective and immunosuppressive TME.

  • TME increases HRS cells growth/survival and decreases anticancer drug activity.

Abstract

Classical Hodgkin lymphoma (cHL) is characterized by few tumor cells surrounded by immune cells, fibroblasts, specialized mesenchymal stromal cells and endothelial cells, representing together with their products an active part of the disease.

Hodgkin and Reed–Sternberg (HRS) cells can secrete cytokines/chemokines and angiogenic factors capable of recruiting and/or inducing the proliferation of the surrounding cells and can also interact with distant sites of the microenvironment by secreting exosomes. To escape from a useful anti-tumor response due to the recognition by T and NK cells, HRS cells down-regulate HLA molecules, produce immune suppressive cytokines that inhibit cytotoxic responses, and induce an immunosuppressive phenotype on T lymphocytes and Monocytes. HRS cells survive, proliferate and are protected from the cytotoxic effects of chemotherapy agents by soluble factors or by the direct contact with inflammatory and stromal cells of the tumor microenvironment (TME).

A summary of the current knowledge about classical Hodgkin Lymphoma focusing on the cross-talk between tumor cells and the microenvironment leading to immune-escape, angiogenesis tumor growth/survival and drug resistance will be reviewed here.

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.

References (111)

  • B.F. Skinnider et al.

    The role of cytokines in classical Hodgkin lymphoma

    Blood

    (2002)
  • E. Maggio et al.

    Chemokines, cytokines and their receptors in Hodgkin's lymphoma cell lines and tissues

    Ann. Oncol

    (2002)
  • A. van den Berg et al.

    High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltratein Hodgkin's lymphoma

    Am. J. Pathol

    (1999)
  • H. Hanamoto et al.

    Expression of CCL28 by Reed-Sternberg cells defines a major subtype of classical Hodgkin's disease with frequent infiltration of eosinophils and/or plasma cells

    Am. J. Pathol

    (2004)
  • K.R. Baumforth et al.

    Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin's lymphoma cells mediates Up-regulation of CCL20 and the migration of regulatory T cells

    Am. J. Pathol

    (2008)
  • F. Jundt et al.

    Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils

    Blood

    (1999)
  • S.A. Meadows et al.

    PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma

    Blood

    (2012)
  • C.W. Fhu et al.

    Reed-Sternberg cell-derived lymphotoxin-alpha activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma

    Blood

    (2014)
  • M. Celegato et al.

    Preclinical activity of the repurposed drug Auranofin in classical Hodgkin lymphoma

    Blood

    (2015)
  • F. Thuma et al.

    Outsmart tumor exosomes to steal the cancer initiating cell its niche

    Semin. Cancer Biol

    (2014)
  • C. Marinaccio et al.

    Insights in Hodgkin Lymphoma angiogenesis

    Leuk. Res

    (2014)
  • F.J. Giles et al.

    Clinical relevance of circulating angiogenic factors in patients with non-Hodgkin's lymphoma or Hodgkin's lymphoma

    Leuk. Res

    (2004)
  • N.A. Marshall et al.

    Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma

    Blood

    (2004)
  • M.R. Zocchi et al.

    High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas

    Blood

    (2012)
  • A. Poggi et al.

    Mechanisms of tumor escape from immune system: role of mesenchymal stromal cells

    Immunol. Lett

    (2014)
  • R. Yamamoto et al.

    PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma

    Blood

    (2008)
  • B.F. Skinnider et al.

    Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma

    Blood

    (2001)
  • C. Renne et al.

    Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma

    Blood

    (2005)
  • P. Fiumara et al.

    Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines

    Blood

    (2001)
  • A. Chiu et al.

    Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL

    Blood

    (2007)
  • B. Lamprecht et al.

    Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha

    Blood

    (2008)
  • C. Mancao et al.

    Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival

    Blood

    (2007)
  • L. Teofili et al.

    Expression of the c-met proto-oncogene and its ligand, hepatocyte growth factor, in Hodgkin disease

    Blood

    (2001)
  • F.Z. Cader et al.

    The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1

    Blood

    (2013)
  • A. Carbone et al.

    Activated DDR1 increases RS cell survival

    Blood

    (2013)
  • F. Jundt et al.

    Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma

    Blood

    (2002)
  • B. Zheng et al.

    MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival

    Blood

    (2003)
  • C.A. de Xavier et al.

    Reed-Sternberg cells form by abscission failure in the presence of functional aurora B kinase

    PLoS ONE

    (2015)
  • B. Rengstl et al.

    Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed-Sternberg cells

    Proc. Natl. Acad. Sci. U.S.A.

    (2013)
  • R. Kuppers et al.

    Hodgkin lymphoma

    J. Clin. Invest

    (2012)
  • S. Kreher et al.

    Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma

    Proc. Natl. Acad. Sci. U.S.A.

    (2014)
  • P.C. Johnson et al.

    Modeling HLA associations with EBV-positive and -negative Hodgkin lymphoma suggests distinct mechanisms in disease pathogenesis

    Int. J. Cancer

    (2015)
  • G. Venkataraman et al.

    Current status of prognostication in classical Hodgkin lymphoma

    Br. J. Haematol

    (2014)
  • D. Aldinucci et al.

    The role of CD40/CD40L and interferon regulatory factor 4 in Hodgkin lymphoma microenvironment

    Leuk. Lymphoma

    (2012)
  • D. Aldinucci et al.

    Expression of CCR5 receptors on Reed-Sternberg cells and Hodgkin lymphoma cell lines: involvement of CCL5/Rantes in tumor cell growth and microenvironmental interactions

    Int. J. Cancer

    (2008)
  • M.C. Assis et al.

    Increased expression of CD4+CD25 +FOXP3+ regulatory T cells correlates with Epstein-Barr virus and has no impact on survival in patients with classical Hodgkin lymphoma in Brazil

    Med. Oncol

    (2012)
  • O. Morales et al.

    Epstein-Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients

    Br. J. Haematol

    (2014)
  • D. Aldinucci et al.

    Interactions between tissue fibroblasts in lymph nodes and Hodgkin/Reed-Sternberg cells

    Leuk. Lymphoma

    (2004)
  • I. Glimelius et al.

    Angiogenesis and mast cells in Hodgkin lymphoma

    Leukemia

    (2005)
  • A.F. Koreishi et al.

    The role of cytotoxic and regulatory T cells in relapsed/refractory Hodgkin lymphoma

    Appl. Immunohistochem. Mol. Morphol

    (2010)
  • Cited by (0)

    View full text