ONCAlert | Upfront Therapy for mRCC

The Emerging Role of Checkpoint Inhibitors in Lymphoid Malignancies

Shipra Gandhi, MD, Pallawi Torka, MD, and Francisco J. Hernandez Ilizaliturri, MD
Published Online: Feb 25,2016

Programmed-Death Pathway

Programmed-death (PD-1, CD 279) is a member of the B7 receptor family, expressed by activated T cells, activated B cells, natural killer cells (NK), and myeloid cells. PD-1 expression is induced when T cells become activated.3 It plays a major role in regulation of immune responses by interacting with 2 ligands, programmed death ligand 1 (PD-L1) (B7-H1 or CD274) and programmed death ligand 2 (PD-L2) (B7-DC or CD273).10 PD-L1 is expressed by B and T cells and macrophages, mediating a generalized anti-inflammatory effect; whereas PD-L2 is expressed by APC10 and regulates T-cell priming.11 These ligands are upregulated by the inflammatory environment and inhibit function of PD-1-bearing lymphocytes. When engaged by one of its ligands, PD-1 inhibits kinases that are involved in T-cell activation through the phosphatase SHP2. In a healthy host, PD-1/PD-L1 signaling regulates effector T-cell responses and protects bystander tissues from immune-mediated damage. This pathway is harnessed by many tumors to evade immune surveillance and forms a major resistance mechanism within the tumor microenvironment.

Mice deficient in PD-1 have an immune phenotype distinct from mice deficient in CTLA-4, as CTLA-4 is believed to primarily regulate early T-cell activation and PD-1 is be- lieved to inhibit T-cell effector activity in the effector phase.12 The inhibition of T-cell activity by PD-1 engagement ap- pears stronger than by CTLA-4 engagement, although the phenotype of PD-1 knockout mice is less severe than that of CTLA-4 knockout.13 The expression of PD-1 is also observed on other immune subsets including T-regulatory (Treg) cells, B cells, and NK cells; Treg cells heavily infiltrate many tumors and suppress effector immune responses, thus PD-1 blockage may also increase antitumor cytotoxicity through increased NK-cell killing and reduction in Treg cell number and function.14,15 PD-1 binds to its ligands PD-L1 and PD-L2 and the interaction results in downstream inhibitory signals resulting in apoptosis of activated T cells.16 Chronic antigen exposure, such as in chronic viral infection or cancer, can lead to persistently high PD-1 expression, which is associated with T-cell exhaustion; blockade of the PD-1/ PD-ligand pathway augmented or restored the function of viral-infection specific and tumor-specific CD4+ and CD8+ T cells in mouse and human studies.3

Expression of PD-1 and Its Ligands in Lymphomas

Lymphomas variably express PD-1 and its ligands.17 PD-1 expression is common among tumor cells in chronic lymphocytic leukemia (CLL) and angioimmunoblastic T-cell lymphoma (AITL) but rare in other NHL subtypes.18,19 PD-1+ T cells are frequently demonstrated in rosettes surrounding Reed-Sternberg (RS) cells in both classical Hodgkin lymphoma (cHL) and nodular lymphocyte subtypes.19,20 PD- L1 expression is common in tumor cells in HL and primary mediastinal B-cell lymphoma (PMBL) where it appears to be associated with amplification in chromosome 9p24.121 and aggressive virus-driven lymphomas.22 A large proportion of cHL tumors have increased surface expression of PD-L1,22 strongly suggesting that HL may have a genetic dependence on the PD-1 pathway for survival. HL is characterized by the presence of few RS cells surrounded by an extensive, but ineffective immune infiltrate. Amplification of 9p24.1 is a recurrent genetic abnormality in HL and mediates PD-L1 and PD-L2 expression.21 PD-1 ligand expression is also increased through the JAK2/STAT pathway, as the extended 9p24.1 amplification region also includes the JAK2 locus.21 In addition, EBV infection, seen commonly in HL also increases PD-1 ligand expression.23 PD-L1 is also expressed on diffuse large B-cell lymphoma (DLBCL) cells and tumor-infiltrating non-malignant cells, primarily macrophages.17,22 Andorsky and colleagues studied PD-L1 expression and functional activity in cell lines and lymphoma specimens.17 PD-L1 was expressed uniformly in anaplastic large cell lymphoma (ALCL) cell lines, but rarely in B-cell NHL. PDL-1 expression in B-cell lymphoma was observed in activated B-cell (ABC) DLBCL. Anti-PD-L1 blocking antibody boosted proliferation and IFN-γ secretion by allogeneic T cells responding to ALCL and DLBCL cells.17

The prognostic implication of PD-1 and its ligand expression on tumor cells in lymphoma is conflicting. In 2 studies, a high proportion of follicular lymphoma (FL) cells expressing PD-1 correlated with a favorable overall survival (OS).20,21 In other reports, the prognostic impact of PD-1 expression was negligible or adverse.22 PD-1 is expressed on tumor-infiltrating lymphocytes (TILs) in DLBCL, and the presence of a large number of PD-1+ TILs is associated with favorable OS in patients with DLBCL.23,24 In a prospective cohort of DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R+CHOP), elevated soluble PD-L1 was adversely prognostic for OS.24 In a recent study describing the clinicopathological impact of PD-L1+ DLBCL, Kiyasu et al defined a new sub-entity termed microenvironmental PD-L1+ (mPD-L11) DLBCL (ie, PD-L1–DLBCL in which PD-L1+ nonmalignant cells are abundant in the tumor microenvironment).25 The prevalence rates of PD-L1+ and mPD-L1+ DLBCL were 11% and 15.3%, respectively. Both PD-L1+ and mPD-L1+ DLBCL were significantly associated with non-germinal center B-cell (GCB) type and Epstein-Barr virus positivity. Patients with PD-L1+ DLBCL had inferior OS compared with patients with PD-L1– DLBCL. In contrast, there was no significant difference in OS between mPD-L1+ and mPD- L1–DLBCL.25

In summary, level of expression of PD-1 and its ligands may be used to guide early development of checkpoint inhibitors in various lymphoma subtypes; however, it is not ready for primetime as either a predictor of response or prognosis.

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The Emerging Role of Checkpoint Inhibitors in Lymphoid Malignancies
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