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Mechanisms of Immune Evasion and Immune Modulation by Lymphoma Cells

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Review

Mechanisms of Immune Evasion and Immune Modulation by Lymphoma Cells

Thomas Menter et al. Front Oncol.

Abstract

Purpose: Targeting cancer cells by modulating the immune system has become an important new therapeutic option in many different malignancies. Inhibition of CTLA4/B7 and PD1/PDL1 signaling is now also being investigated and already successfully applied to various hematologic malignancies.

Methods: A literature review of PubMed and results of our own studies were compiled in order to give a comprehensive overview on this topic.

Results: We elucidate the pathophysiological role of immunosuppressive networks in lymphomas, ranging from changes in the cellular microenvironment composition to distinct signaling pathways such as PD1/PDL1 or CTLA4/B7/CD28. The prototypical example of a lymphoma manipulating and thereby silencing the immune system is Hodgkin lymphoma. Also other lymphomas, e.g., primary mediastinal B-cell lymphoma and some Epstein-Barr virus (EBV)-driven malignancies, use analogous survival strategies, while diffuse large B-cell lymphoma of the activated B-cell type, follicular lymphoma and angioimmunoblastic T-cell lymphoma to name a few, exert further immune escape strategies each. These insights have already led to new treatment opportunities and results of the most important clinical trials based on this concept are briefly summarized. Immune checkpoint inhibition might also have severe side effects; the mechanisms of the rather un(der)recognized hematological side effects of this treatment approach are discussed.

Conclusion: Silencing the host's immune system is an important feature of various lymphomas. Achieving a better understanding of distinct pathways of interactions between lymphomas and different immunological microenvironment compounds yields substantial potential for new treatment concepts.

Keywords: CD58; CD70; Epstein–Barr virus; HLA-G; PD1; PDL1; lymphoma; microenvironment.

Figures

Figure 1
Figure 1
(A) PDL1 expression study of classical Hodgkin lymphoma with PDL1 (red chromogen)-MUM1p (brown chromogen) double-staining; note that a lot of PDL1+ cells, corresponding to tumor-infiltrating macrophages, do not express MUM1p while yielding dendroid cytoplasmic projections and form “immunosuppressive microniches,” in which PDL1 and MUM1p co-expressing Hodgkin- and Reed–Sternberg cells (see also inset) are scattered. (B) PD1 expression by single tumor cells (large ones) and plenty of tumor-infiltrating lymphocytes in T-cell- and histiocyte-rich B-cell lymphoma.
Figure 2
Figure 2
(A) Amplification of the PDL1/JAK2 locus at 9p24 in a primary mediastinal B-cell lymphoma (PMBCL); note multiple green FISH signals corresponding to the locus of interest compared to only 2 red centromere 9 signals/cell. (B) Rearrangement of the CIITA locus at 16p13 a PMBCL; note fused green and red signals corresponding to the non-rearranged wild-type allele and free green and red signals corresponding to the rearranged allele.
Figure 3
Figure 3
(A) Expression of HLA-G in a diffuse large B-cell lymphoma. (B) Expression of HLA-G by Hodgkin- and Reed–Sternberg cells of classical Hodgkin lymphoma.
Figure 4
Figure 4
Expression of CD70 in a testicular diffuse large B-cell lymphoma; note a negative seminiferous canaliculus.
Figure 5
Figure 5
Schematic summary of mechanisms discussed in this review lymphoma cells employ to influence or circumvent the immune system; molecules that are rather repressed are in italics; genes inactivated by mutations are in white color, while those activated are in orange.

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