Page 20 - Haematologica August 2018

Correspondence:
roch.houot@chu-rennes.fr
Received: February 1, 2018. Accepted: April 24, 2018. Pre-published: July 13, 2018.
doi:10.3324/haematol.2017.184192
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/8/01256
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Hide or defend, the two strategies of lymphoma immune evasion: potential implications for immunotherapy
Marie de Charette1 and Roch Houot1,2
1CHU Rennes, Service Hématologie Clinique, F-35033 and 2INSERM, U1236, F-35043, France
ABSTRACT
Evading immune eradication is a prerequisite for neoplastic progres- sion and one of the hallmarks of cancer. Here, we review the differ- ent immune escape strategies of lymphoma and classify them into two main mechanisms. First, lymphoma cells may “hide” to become invisible to the immune system. This can be achieved by losing or down- regulating MHC and/or molecules involved in antigen presentation (including antigen processing machinery and adhesion molecules), there- by preventing their recognition by the immune system. Second, lym- phoma cells may “defend” themselves to become resistant to immune eradication. This can be achieved in several ways: by becoming resistant to apoptosis, by expressing inhibitory ligands that deactivate immune cells and/or by inducing an immunosuppressive (humoral and cellular) microenvironment. These immune escape mechanisms may have thera- peutic implications. Their identification may be used to guide “personal- ized immunotherapy” for lymphoma.
Introduction
Since the hypothesis of “cancer immunosurveillance” proposed by Burnet and Thomas about 60 years ago,1 our knowledge about the interactions between cancer cells and the host immune system has dramatically increased. These interactions, referred to as “immunoediting”, are summarized in the three “Es” theory: Elimination, Equilibrium and Escape.2 Because of: i) genetic instability and tumor heterogeneity; and ii) immune selection pressure, tumor cells become progressively capable of avoid- ing immune destruction during carcinogenesis. This property of cancer cells is now recognized as a hallmark of cancer.3
The generation of an antitumor immune response requires several steps, elegantly summarized in the “cancer immunity cycle”.4 It consists of the release of tumor anti- gens (Ag), their capture by professional antigen-presenting cells (APC), and the priming of T cells. Then, effector T cells traffic to the tumor site, and recognize and kill cancer cells. To be effective, the priming of T cells needs two signals: i) the recognition of the MHC-Ag complex by the T-cell receptor (TCR) (signal 1); and ii) the co-stimulation by the CD80/CD86 molecules of CD28 (signal 2). Signal 1 without signal 2 leads to T-cell anergy.5 Only professional APC express both class I (MHC-I) and class II (MHC-II) major histocompatibility complex, and co-stimulatory molecules. All nucleated cells present endogenous Ag to CD8 T cells through MHC-I. Professional APC present exogenous Ag to CD4 T cells through MHC-II, but also exogenous Ag to CD8 T cells through MHC-I, a process called cross-presentation.6 B-cell lymphomas are unique among cancers because the tumor cells themselves are professional APC.7 With the advent of new immunotherapies including checkpoint inhibitors, bispecific antibodies and CAR T cells, understanding lymphoma immunity and immune evasion may be crucial to determine the optimal treatment and/or combinations for a given patient.
Here, we review the different immune escape strategies of lymphoma and classify them into two main mechanisms. First, lymphoma cells may “hide” to become invis- ible to the immune system. Second, lymphoma cells may “defend” themselves to become resistant to immune eradication. Finally, we discuss how the understanding of
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