CD84 regulates PD-1/PD-L1 expression and function in chronic lymphocytic leukemia
Hadas Lewinsky, Avital F. Barak, Victoria Huber, Matthias P. Kramer, Lihi Radomir, Lital Sever, Irit Orr, Vita Mirkin, Nili Dezorella, Mika Shapiro, Yosef Cohen, Lev Shvidel, Martina Seiffert, Yair Herishanu, Shirly Becker-Herman, Idit Shachar
Hadas Lewinsky, Avital F. Barak, Victoria Huber, Matthias P. Kramer, Lihi Radomir, Lital Sever, Irit Orr, Vita Mirkin, Nili Dezorella, Mika Shapiro, Yosef Cohen, Lev Shvidel, Martina Seiffert, Yair Herishanu, Shirly Becker-Herman, Idit Shachar
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Research Article Immunology Oncology

CD84 regulates PD-1/PD-L1 expression and function in chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and progressive accumulation of mature B lymphocytes in the peripheral blood, lymphoid tissues, and bone marrow. CLL is characterized by profound immune defects leading to severe infectious complications. T cells are numerically, phenotypically, and functionally highly abnormal in CLL, with only limited ability to exert antitumor immune responses. Exhaustion of T cells has also been suggested to play an important role in antitumor responses. CLL-mediated T cell exhaustion is achieved by the aberrant expression of several inhibitory molecules on CLL cells and their microenvironment, prominently the programmed cell death ligand 1/programmed cell death 1 (PD-L1/PD-1) receptors. Previously, we showed that CD84, a member of the SLAM family of receptors, bridges between CLL cells and their microenvironment. In the current study, we followed CD84 regulation of T cell function. We showed that cell-cell interaction mediated through human and mouse CD84 upregulates PD-L1 expression on CLL cells and in their microenvironment and PD-1 expression on T cells. This resulted in suppression of T cell responses and activity in vitro and in vivo. Thus, our results demonstrate a role for CD84 in the regulation of immune checkpoints by leukemia cells and identify CD84 blockade as a therapeutic strategy to reverse tumor-induced immune suppression.

Authors

Hadas Lewinsky, Avital F. Barak, Victoria Huber, Matthias P. Kramer, Lihi Radomir, Lital Sever, Irit Orr, Vita Mirkin, Nili Dezorella, Mika Shapiro, Yosef Cohen, Lev Shvidel, Martina Seiffert, Yair Herishanu, Shirly Becker-Herman, Idit Shachar

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Figure 3

Decreased PD-L1 expression in vivo on Eμ-TCL1 cells derived from CD84–/– mice.

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Decreased PD-L1 expression in vivo on Eμ-TCL1 cells derived from CD84–/–...
(A–E) Eμ-TCL1 splenocytes (4 × 107) were injected i.v. into the tail vein of C57BL/6 WT or CD84–/– mice. After 14 to 21 days, the mice were sacrificed, and expression of PD-L1 was determined by flow cytometry on CD5/CD19 Eμ–TCL1 cells in (A) PB (n = 8–10), (B) spleen (n = 12–14), (C) peritoneum (n = 6–10), (D) BM (n = 7–10), and (E) LNs (n = 7–8). A representative histogram of PD-L1 expression on PB cells is shown in A. ***P < 0.001, 2-tailed t test (A), ****P < 0.0001, 2-tailed t test (B–D), and P = 0.9893 (NS), 2-tailed t test (E). (F and G) BM cells (5 × 106) derived from 8-week-old Eμ-TCL1 mice or negative control littermates (WT) were injected into lethally irradiated C57BL/6 (WT) or CD84-deficient (CD84–/–) mice. After 6 months, the mice were euthanized, and the expression of PD-L1 was determined on Eμ-TCL1 cells in the (F) peritoneum (n = 3–4) and (G) spleen (n = 3–4). *P < 0.05, 2-tailed t test. (H) C57BL/6 mice were injected with 4 × 107 Eμ-TCL1 splenocytes and, starting from the second day, were treated i.v. with 1  mg/kg body weight B4 or isotype control antibodies. After 14 days, the mice were sacrificed, and PD-L1 expression was determined on CD5+CD19+ peritoneal cells (n = 4; **P < 0.01, 1-tailed t test).