Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells

Abstract Backgrounds Wilms’ tumor gene 1 (WT1) peptide vaccine and anti-programmed cell death-1 (PD-1) antibody are expected as immunotherapies to improve the clinical outcome of glioblastoma. The aims of this study were to clarify how each immunotherapy affect tumor-infiltrating immune cells (TIIs) and to determine whether the combination of these two therapies could synergistically work. Methods Mice were transplanted with WT1 and programed cell death-ligand 1 (PD-L1) doubly expressing glioblastoma cells into brain followed by treatment with WT1 peptide vaccine, anti-PD-1 antibody, or the combination of the two, and survival of each therapy was compared. CD45 + cells were positively selected as TIIs from the brains with tumors, and TIIs were compared between WT1 peptide vaccine and anti-PD-1 antibody therapies. Results Most mice seemed to be cured by the combination therapy with WT1 peptide vaccine and anti-PD-1 antibody, which was much better survival than each monotherapy. A large number of CD4 + T cells, CD8 + T cells, NK cells including WT1-specific CD8 + and CD4 + T cells infiltrated into the glioblastoma in WT1 peptide vaccine-treated mice. On the other hand, the number of TIIs did not increase, but instead PD-1 molecule expression was decreased on the majority of the tumor-infiltrating CD8 + T cells in the anti-PD-1 antibody-treated mice. Conclusion Our results clearly demonstrated that WT1 peptide vaccine and anti-PD-1 antibody therapies worked in the different steps of cancer-immunity cycle and that the combination of the two therapies could work synergistically against glioblastoma.

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Activation of CD8 T cells accelerates anti-PD-1 antibody-induced psoriasis-like dermatitis through IL-6

Communications Biology ◽

10.1038/s42003-020-01308-2 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Ryota Tanaka ◽

Yuki Ichimura ◽

Noriko Kubota ◽

Akimasa Saito ◽

Yoshiyuki Nakamura ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Programmed Cell Death ◽

Adverse Events ◽

Cd8 T Cells ◽

Murine Model ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Skin Inflammation ◽

Programmed Cell Death 1

Abstract Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events (irAEs) including psoriasis-like dermatitis. Our observations on human samples indicated enhanced epidermal infiltration of CD8 T cells, and the pathogenesis of which appears to be dependent on IL-6 in the PD-1 signal blockade-induced psoriasis-like dermatitis. By using a murine model of imiquimod-induced psoriasis-like dermatitis, we further demonstrated that PD-1 deficiency accelerates skin inflammation with activated cytotoxic CD8 T cells into the epidermis, which engage in pathogenic cross-talk with keratinocytes resulting in production of IL-6. Moreover, genetically modified mice lacking PD-1 expression only on CD8 T cells developed accelerated dermatitis, moreover, blockade of IL-6 signaling by anti-IL-6 receptor antibody could ameliorate the dermatitis. Collectively, PD-1 signal blockade-induced psoriasis-like dermatitis is mediated by PD-1 signaling on CD8 T cells, and furthermore, IL-6 is likely to be a therapeutic target for the dermatitis.

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Follicular Helper T Cells Remodel the Immune Microenvironment of Pancreatic Cancer via Secreting CXCL13 and IL-21

Cancers ◽

10.3390/cancers13153678 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3678

Author(s):

Xuan Lin ◽

Longyun Ye ◽

Xu Wang ◽

Zhenyu Liao ◽

Jia Dong ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

B Cells ◽

Tumor Microenvironment ◽

Programmed Cell Death ◽

Cd8 T Cells ◽

Helper T Cells ◽

Tfh Cells ◽

Follicular Helper ◽

Programmed Cell Death 1

Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play an anti-tumor role in various malignant solid tumors and predict better patient prognosis. In the present study, we aimed to determine the immunosuppressive mechanism associated with Tfh cells and explore a new strategy to improve the tumor microenvironment of PDAC. Flow cytometry was used to detect the infiltration and proportion of Tfh cells in tumor tissues and peripheral blood from patients with PDAC. The spatial correlations of Tfh cells with related immune cells were evaluated using immunofluorescence. The function of Tfh cells was examined using in vitro and in vivo model systems. The high infiltration of Tfh cells predicted better prognosis in patients with PDAC. Tfh cells recruited CD8+ T cells and B cells by secreting C-X-C motif chemokine ligand 13 (CXCL13), and promoted the maturation of B cells into antibody-producing plasma cells by secreting interleukin 21 (IL-21), thereby promoting the formation of an immunoactive tumor microenvironment. The function of Tfh cells was inhibited by the programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD-1) signaling pathway in PDAC, which could be reversed using neoadjuvant chemotherapy. Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8+ T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.

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Interaction of Programmed Cell Death-1 (PD-1) with its Ligand PD-ligand 1 (PD-L1) has a Co-inhibitory Function in T Cells During Human Tuberculosis

Clinical Immunology ◽

10.1016/j.clim.2010.03.213 ◽

2010 ◽

Vol 135 ◽

pp. S70

Author(s):

Dipendra Mitra ◽

Amar Singh ◽

Surendra Sharma

Keyword(s):

T Cells ◽

Cell Death ◽

Programmed Cell Death ◽

Inhibitory Function ◽

Programmed Cell Death 1

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Side effects of immune-checkpoint inhibitors: Can multiple side effects be seen in a patient?

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211038136 ◽

2021 ◽

pp. 107815522110381

Author(s):

Esra Özyurt ◽

Serhat Özçelik ◽

Heves Sürmeli ◽

Mehmet Çelik ◽

Murat Ayhan ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Side Effects ◽

Programmed Cell Death ◽

Adverse Events ◽

Checkpoint Inhibitors ◽

Host Cells ◽

Immunoglobulin G4 ◽

Programmed Cell Death 1 ◽

Recurrent Renal Cell Carcinoma

Introduction Nivolumab is a human immunoglobulin G4 monoclonal antibody that inhibits programmed cell death-1 activity by binding to the programmed cell death-1 receptors. Cancer cells express increased number of programmed cell death-1 ligands and this allows them to escape the cytotoxic effects of the T cells. Therefore, the negative programmed cell death-1 receptor signal regulates T-cell proliferation and activation is disrupted. However, this change in the activity of the T cells can cause them to lose their ability to recognize host cells. The immune response enabled by these agents has led to side effects, commonly known as “immune-related adverse events.” Case report We report a case of a 66-year-old male patient who was treated with nivolumab for recurrent renal cell carcinoma presented with hepatitis and adrenalitis. Three weeks after starting nivolumab, the patient had abdominal pain and weakness, and then aspartate and alanine transaminase levels were found to be elevated. Management and outcome Hepatitis was predicted to be due to nivolumab, because other causes were excluded. He started using oral methylprednisolone and then, hepatitis improved. However, while receiving methylprednisolone treatment, fludrocortisone was started with the pre-diagnosis of adrenalitis due to the persistence of fatigue, weakness, and hyponatremia and hyperkalemia. With both treatments, the patient's symptoms and sodium and potassium level returned to normal. Discussion This case emphasizes the need for patient's education and awareness of immune-related adverse events, and the importance of understanding the management of life-threatening complications of the checkpoint inhibitors, because these side effects require prompt recognition and treatment.

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