Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice.

Loss of Kif18A Results in Spindle Assembly Checkpoint Activation at Microtubule-Attached Kinetochores.

The spindle assembly checkpoint (SAC) halts anaphase progression until all kinetochores have obtained bipolar, stable attachments to the mitotic spindle. Upon initial attachment, chromosomes undergo oscillatory movements to reach metaphase. Once a chromosome is correctly attached and positioned, these oscillatory movements are reduced by the motor protein Kif18A, and loss of Kif18A results in chromosome hyper-oscillations.

BUB1 Is Essential for the Viability of Human Cells in which the Spindle Assembly Checkpoint Is Compromised.

The spindle assembly checkpoint (SAC) ensures faithful segregation of chromosomes. Although most mammalian cell types depend on the SAC for viability, we found that human HAP1 cells can grow SAC independently. We generated MAD1- and MAD2-deficient cells and mutagenized them to identify synthetic lethal interactions, revealing that chromosome congression factors become essential upon SAC deficiency.

The immune system in cancer metastasis: friend or foe?

Metastatic disease is the leading cause of death among cancer patients and involves a complex and inefficient process. Every step of the metastatic process can be rate limiting and is influenced by non-malignant host cells interacting with the tumor cell. Over a century ago, experiments first indicated a link between the immune system and metastasis.