Immune evasion of mantle cell lymphoma: expression of B7-H1 leads to inhibited T-cell response to and killing of tumor cells

Abstract

Clinical trials of immunotherapy in mantle cell lymphoma have not yet delivered desirable results, partly because of the inhibitory machinery of the tumor and its microenvironment. Here we investigated the role of B7-H1, a member of the B7 family of co-stimulatory/co-inhibitory ligands, in mantle cell lymphoma-mediated immunosuppression. Allogeneic CD3 + , CD4+ and CD8 + T cells were purified and co-cultured with irradiated mantle cell lymphoma cells. Mantle cell lymphoma-reactive T-cell lines from HLA-A*0201 + healthy blood donors were generated after in vitro restimulation, and were subjected to functional tests. We found that B7-H1 expressed on mantle cell lymphoma cells was able to inhibit T-cell proliferation induced by the tumor cells, impair the generation of antigen-specific T-cell responses, and render mantle cell lymphoma cells resistant to T-cell-mediated cytolysis. Blocking or knocking down B7-H1 on mantle cell lymphoma cells enhanced T-cell responses and restored tumor-cell sensitivity to T-cell-mediated killing in vitro and in vivo. Knocking down B7-H1 on mantle cell lymphoma cells primed more CD4 + or CD8 + memory effector T cells. Our study demonstrates for the first time that lymphoma cell-expressed B7-H1 may lead to the suppression of host anti-tumor immune responses in mantle cell lymphoma and targeting tumor cell B7-H1 may represent a novel approach to improve the efficacy of immunotherapy in patients with mantle cell lymphoma.

Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas

“…38,39 The IEGS33 scores of BL were slightly higher (mean SES D 0.6), suggesting that these lymphoma escape immunity through different pathways. 40,41 Low scores were also found in most but not all MCL 42,43 that included PD1 defects and autoimmunity in MZL. 44,45 In contrast, IEGS33 scores were significantly elevated in 73% of FL (mean SE D 1.4) and 78% of DLBCL (mean SES D 1.6) (Fig.…”

The emerging role of immune checkpoint inhibition in malignant lymphoma

“…49 PD-L1 expressed by MCL cell lines results in impaired T-cell proliferation after tumor exposure, impaired T-cell-mediated tumor cytotoxicity and inhibited specific anti-tumor T-cell responses. 50 So far, data available on ICI in MCL are limited: in the aforementioned ipilimumab phase I study, 46 the only MCL patient included did not respond to treatment. In contrast, a PR was observed in a single MCL patient treated with ipilimumab for relapse after allogeneic SCT.…”

“…47 Results of currently ongoing combination trials with nivolumab and ipilimumab or anti-KIR therapy are pending (Table 2). In addition to the clinical efficacy of single-agent brutonkinase inhibition in MCL, 50,51 combinations of ibrutinib and ICI look appealing, in light of the immunomodulatory effect targeting interleukin-2-inducible T-cell kinase.…”

T-Cell Levels Are Prognostic in Mantle Cell Lymphoma

“…17), are strongly associated with outcome. MCL cells are dependent on signals from stromal cells and cytokines in the microenvironment for their survival (18)(19)(20)(21)(22). However, compared with follicular lymphoma (FL) and chronic lymphocytic lymphoma/small cell lymphoma (CLL/SLL), much less is known about how the nonmalignant cells affect disease development and prognosis in MCL.…”