IL-2 based cancer immunotherapies: an evolving paradigm.

Discovered over 4 decades ago in the supernatants of activated T cells, interleukin-2 (IL-2) is a potent pleiotropic cytokine involved in the regulation of immune responses. It is required for effector T cell expansion and differentiation as well as for peripheral tolerance induced by regulatory T cells. High-dose IL-2 treatment was the first FDA-approved immunotherapy for renal cell carcinoma and melanoma, achieving single agent complete and durable responses, albeit only in a small proportion of patients.

An orthogonal IL-2 and IL-2Rβ system drives persistence and activation of CAR T cells and clearance of bulky lymphoma.

Chimeric antigen receptor (CAR) T cells induce durable responses in patients with refractory hematological tumors. However, low CAR T cell activity, poor engraftment, or short in-patient persistence can lead to tumor progression or relapse. Furthermore, excessive CAR T cell expansion and activation can result in life-threatening cytokine release syndrome (CRS).

Autochthonous T cells to the rescue: IL-10 directly activates tumor-resident CD8(+) T cells.

Successful cancer immunotherapy is thought to require de novo priming of tumor specific CD8(+) T cells in lymphatic organs. Contrasting these beliefs, cancer therapy based on interleukin-10 (IL-10) results in tumor rejection without a requirement for T-cell trafficking from lymphatic organs. Rather, IL-10 directly activates autochthonous, tumor-resident CD8(+) T cells.

Killing from within.

Interleukin-10 (IL-10) is considered to be an immunosuppressive cytokine. However, the continuous administration of pegylated IL-10 (PEG-IL10) leads to the rejection of large, firmly established and metastatic syngeneic tumors. PEG-IL10 therapy induces the expansion and activation of intratumoral, tumor antigen-specific CD8(+) T cells, leading to interferon γ (IFNγ)-mediated Th1 like immunity and tumor rejection.

IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs.

The presence of activated intratumoral T cells correlates clinically with better prognosis in patients with cancer. Although tumor vaccines can increase the number of tumor-specific CD8(+) T cells in systemic circulation, they frequently fail to increase the number of active and tumor reactive T cells within the tumor. Here we show that treatment with the pleiotropic cytokine interleukin-10 (IL-10) induces specific activation of tumor-resident CD8(+) T cells as well as their intratumoral expansion in several mouse tumor models.

IL-10 elicits IFNγ-dependent tumor immune surveillance.

Tumor immune surveillance and cancer immunotherapies are thought to depend on the intratumoral infiltration of activated CD8(+) T cells. Intratumoral CD8(+) T cells are rare and lack activity. IL-10 is thought to contribute to the underlying immune suppressive microenvironment.

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance.

Recognition of self-antigen-derived epitopes presented by major histocompatibility complex class II (MHC II) molecules on thymic epithelial cells (TECs) is critical for the generation of a functional and self-tolerant CD4 T-cell repertoire. Whereas haematopoietic antigen-presenting cells generate MHC-II-peptide complexes predominantly through the processing of endocytosed polypeptides, it remains unknown if and how TECs use unconventional pathways of antigen presentation. Here we address the role of macroautophagy, a process that has recently been shown to allow for endogenous MHC II loading, in T-cell repertoire selection in the mouse thymus.

Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells.

The parameters specifying whether autoreactive CD4(+) thymocytes are deleted (recessive tolerance) or differentiate into regulatory T cells (dominant tolerance) remain unresolved. Dendritic cells directly delete thymocytes, partly through cross-presentation of peripheral antigens 'promiscuously' expressed in medullary thymic epithelial cells (mTECs) positive for the autoimmune regulator Aire. It is unclear if and how mTECs themselves act as antigen-presenting cells during tolerance induction.

Cyclin D does not provide essential Cdk4-independent functions in Drosophila.

The three mammalian D-type cyclins are thought to promote progression through the G1 phase of the cell cycle as regulatory subunits of cyclin-dependent kinase 4 and 6. In addition, they have been proposed to control the activity of various transcription factors without a partner kinase. Here we describe phenotypic consequences of null mutations in Cyclin D, the single D-type cyclin gene in Drosophila.

Drosophila p27Dacapo expression during embryogenesis is controlled by a complex regulatory region independent of cell cycle progression.

dacapo encodes a CIP/KIP-type inhibitor of Cyclin E/Cdk2 complexes in Drosophila melanogaster. In the embryonic epidermis, dacapo expression starts during G2 of the final division cycle and is required for the arrest of cell cycle progression in G1 after the final mitosis. The onset of dacapo transcription is the earliest event known to be required for the epidermal cell proliferation arrest.