PD-1 Receptor Inhibitors Exacerbate T-Cell Related Tumor Growth

PD-1, or programmed cell death receptor 1, is a receptor protein present on the surface of T-cells. Its main purpose, is to inhibit T-cell receptor signaling and activity in prevention of T-cell hyper activation and autoimmune attack. This occurs when another cell which expresses the PD-1 ligand combines with the PD-1 receptor on a T-cell and induces a downstream signaling cascade involving suppressive pathways such as PI3K and NfKβ. Unfortunately, tumor cells also express the PD-1 ligand on their surfaces, making it easy for them to bind with PD-1 receptors an inhibit T-Cell activation, therefore eliminating the immune systems ability to defend against tumors. To circumvent this issue, clinicians commonly use antibodies which target and block PD-1 receptors on T-cells, ensuring that they do not bind to their ligand, and in turn, remain constitutively active and engaged in immune attack against tumor cells. This anti-PD-1 receptor antagonist has become a common treatment used by clinicians to treat all sorts of cancers, however, recently researchers have noticed that this therapy has extremely negative effects on the treatment of T-cell specific cancers, such as T-cell Non-Hodgkins Lymphoma (NHL). In order to identify why anti-PD-1 receptor antagonists increase tumor cell proliferation in T-cell NHL, researchers undertook an analysis of the PD-1 signaling pathway in precancerous T cells in mice. Interestingly, they were able to identify that within T-cells, certain oncogenes were able to upregulate the expression of PD-1 receptors. Therefore, when an anti- PD-1 receptor antibody bound to the PD-1 receptors on the surface of precancerous T cells, they became constitutively active and proliferated uncontrollably. This study has identified that the common cancer treatment, anti-PD1 receptor antagonists, are actually able to increase the proliferation of cancerous T cells and enhance T-cell NHL progression. Therefore, any future patient diagnosed with T cell related cancers will now not receive this therapy and have a much higher chance of overall survival and remission.

Reference

• Wartewig, Tim, et al. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552.7683 (2017): 121.

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