Therapy of lymphoma by immune checkpoint inhibitors: the role of T cells, NK cells and cytokine-induced tumor senescence

Abstract

BackgroundAlthough antibodies blocking immune checkpoints have already been approved for clinical cancer treatment, the mechanisms involved are not yet completely elucidated. Here we used a λ-MYC transgenic model of endogenously growing B-cell lymphoma to analyze the requirements for effective therapy with immune checkpoint inhibitors.MethodsGrowth of spontaneous lymphoma was monitored in mice that received antibodies targeting programmed cell death protein 1 and cytotoxic T lymphocyte-associated protein-4, and the role of different immune cell compartments and cytokines was studied by in vivo depletion experiments. Activation of T and natural killer cells and the induction of tumor senescence were analyzed by flow cytometry.ResultsOn immune checkpoint blockade, visible lymphomas developed at later time points than in untreated controls, indicating an enhanced tumor control. Importantly, 20% to 30% of mice were even long-term protected and did never develop clinical signs of tumor growth. The therapeutic effect was dependent on cytokine-induced senescence in malignant B cells. The proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor (TNF) were necessary for the survival benefit as well as for senescence induction in the λ-MYC model. Antibody therapy improved T-cell functions such as cytokine production, and long-time survivors were only observed in the presence of T cells. Yet, NK cells also had a pronounced effect on therapy-induced delay of tumor growth. Antibody treatment enhanced numbers, proliferation and IFN-γ expression of NK cells in developing tumors. The therapeutic effect was fully abrogated only after depletion of both, T cells and NK cells, or after ablation of either IFN-γ or TNF.ConclusionsTumor cell senescence may explain why patients responding to immune checkpoint blockade frequently show stable growth arrest of tumors rather than complete tumor regression. In the lymphoma model studied, successful therapy required both, tumor-directed T-cell responses and NK cells, which control, at least partly, tumor development through cytokine-induced tumor senescence.

Cytokine-Induced Senescence in the Tumor Microenvironment and Its Effects on Anti-Tumor Immune Responses

“…Induction of senescence (via p16 or p21 upregulation) [26,126] Human cancer cell lines (bladder, melanoma, and breast) IL-2/IL-12/IL-18-stimulated γδ T cells (via secretion of IFN-γ + TNF) Induction of senescence (via p21 upregulation) [109] Human melanoma cell lines Co-culture-derived supernatants from nonclassical monocytes (slanMo) and NK cells (via secretion of IFN-γ + TNF) Induction of senescence (via p21 upregulation) [120] Murine aortic endothelial cells (MAECs) Th17 cells/IL-17A Induction of senescence (via NF-κB/p53/Rb pathway) [124] Human breast cancer cell line IL-32θ Induction of senescence (mechanism unclear) [125] In addition to the direct effects of the cytokines, immune-mediated cancer control and senescence induction can also be achieved and reinforced by the use of immune checkpoint inhibitors [26]. While blocking antibodies directed against LAG-3 and PD-L1 were sufficient to induce senescence in tumor cells, a combination with an adoptive transfer of TAA-specific Th1 cells further increased this effect.…”

“…These findings clearly demonstrated that interfering with negative regulators of the immune system either expressed on certain immune cells (i.e., LAG-3) or on tumor cells (i.e., PD-L1) is able to restore an anti-tumor response that induces protective cancer control through the senescence barrier that leads to a stable growth arrest instead of a complete regression. Recent reports further showed the consequences of immune checkpoint blockade (ICB) on other cell types upon treatment in a mouse lymphoma model [126,127]. The antibodies used for ICB had, for instance, favorable effects on immune cells.…”

“…T cells showed an improved function (e.g., by their cytokine production) and were relevant for longtime survival, whereas NKs also contributed to delayed tumor progression, as their number increased upon ICB treatment, as did their proliferation and production of IFN-γ. Therefore, tumor development in ICB responders is controlled by T cells and NKs that produce effector cytokines leading to tumor cell senescence [126]. Moreover, ICB also exerted an influence on DCs: in response to IFNγ produced by T cells and NKs, tumor-infiltrating DCs expressed more co-stimulatory molecules and a higher IL-12/IL-10 ratio.…”

IL-2 Combined with IL-15 Enhanced the Expression of NKG2D Receptor on Patient Autologous NK Cells to Inhibit Wilms’ Tumor via MAPK Signaling Pathway

“…In order to explore the potential of immunotherapy strategy on WT, cytokine therapy-induced NK cell functions are likely to affect the clinical course of several human malignancies, including neuroblastoma, gastrointestinal sarcoma, and kidney and lung carcinoma [34,35]. In this study, WT patient autologous PBMCs were stimulated by IL-2 combination with IL-15.…”

Relationship and prognostic significance of IL-33, PD-1/PD-L1, and tertiary lymphoid structures in cervical cancer

“…In this microenvironment, immune response participates in regulating tumor progression. [7][8][9] Immune checkpoint inhibitors as important emerging treatment modality in cancer therapy, particularly programmed cell death-1/ligand-1(PD-1/PD-L1) immune checkpoint inhibitors. 10,11 PD-1 is a key inhibitory receptor expressed by activated T and B cells.…”