Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma

Abstract

Classical Hodgkin lymphoma (cHL) is an unusual B-cell-derived malignancy in which rare malignant Hodgkin and Reed-Sternberg (HRS) cells are surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. This striking feature suggests that malignant HRS cells escape immunosurveillance and interact with immune cells in the cancer microenvironment for survival and growth. We previously found that cHLs have a genetic basis for immune evasion: near-uniform copy number alterations of chromosome 9p24.1 and the associated PD-1 ligand loci, CD274/PD-L1 and PDCD1LG2/PD-L2, and copy number-dependent increased expression of these ligands. HRS cells expressing PD-1 ligands are thought to engage PD-1 receptor-positive immune effectors in the tumor microenvironment and induce PD-1 signaling and associated immune evasion. The genetic bases of enhanced PD-1 signaling in cHL make these tumors uniquely sensitive to PD-1 blockade.

Figure 1.

PD-1 signaling. Modified version reprinted with permission from Baumeister, SH et al, 2016; Annu. Rev. Immunol. 34:539-73.

Figure 2.

PD-L1 and PD-L2 copy gain and further induction via JAK2/STAT signaling. (Left) The 9p24.1 amplicon in cHL includes PD-L1, PD-L2, and JAK2. (Right) JAK2 copy gain leads to increased JAK2 protein expression and enhanced JAK/STAT signaling, which further induces PD-1 ligand expression.

Figure 3.

Genetic and immunohistochemical analyses of the PD-L1 and PD-L2 loci. (A) Location and color-labeling of the BAC clones on 9p24.1 used for FISH. RP11-599H20 including PD-L1, labeled red. RP11-635N21 including PD-L2, labeled green. (B) Representative images of FISH results for the different categories. PD-L1 in red, PD-L2 in green, fused (F) signals in yellow and centromeric probe (CEP9) in aqua (A). In these images, disomy reflects 2A:2F; polysomy, 3A:3F; copy gain, 3A:6F; and amplification, 15+F. (C) PD-L1 (brown)/PAX5 (red) immunohistochemistry in the cHL cases with 9p24.1 disomy, polysomy, copy gain, and amplification from panel B. Scale bar indicates 50 μm. Reprinted with permission © (2016) American Society of Clinical Oncology. All rights reserved. Roemer, MG et al: J Clin Oncol Vol. 34 (23), 2016 2690-7.

Figure 4.

β2M, MHC class I, and MHC class II expression in cHL patients. (A) β2M and MHC class I immunohistochemical staining in 4 representative cHL patients: #1, positive for both markers (Pos); #2, decreased for both markers (Dec); #3 and #4, negative for both markers (Neg). Individual HRS cells are depicted with a black arrow. The white arrows indicate expression on surrounding, nonmalignant inflammatory cells. Scale bar, 50 μm. (B) Heat map representing the distribution of β2M and MHC class I (MHC-I) expression in the 108 cHL patients. White, negative; gray, decreased; black, positive; hatched, not assessable (NA). Reprinted with permission from Cancer Immunology Research 2016; 4: 910.