If you’ve been following developments in cancer immunotherapy closely, you’ve probably heard of programmed death 1 (PD1/PDCD1, also known as CD279) and PDL1 (CD274). Their interaction is at the center of new immune checkpoint-targeting therapies coming out of the pharmaceutical industry, such as Bristol-Myers Squibb’s nivolumab and Merck’s pembrolizumab (1, 5). What are PD1 and PDL1, and what do they do to advance cancer? And importantly, what work remains to be done in the translational research sphere? Let’s start with a brief discussion of immune checkpoints and the PD1-PDL1 interaction, then move on to some of the important aspects involved in studying them.
Switching on T cells
Immune checkpoints are of significant interest as targets for cancer immunotherapy. They’re the on-off switches that control T cell immune responses, and are essential for protecting the body from the damage that an out-of-control immune response could cause. PD1 and PDL1 are one such immune checkpoint; PD1 is present on T cells, and PDL1 on other “self” cells in the body. When they interact, the T cell response switches off, essentially acknowledging that the PDL1-bearing cell isn’t a foreign invader. How does this tie in to immuno-oncology? Simple. Cancer cells often produce large quantities of PDL1, which enables them to escape immune control. This discovery has led to a race to find appropriate blockers for the PD1-PDL1 interaction (2–4).
Translational research – biomarkers and more
Despite the progress in blocking this interaction in drug development, questions remain. What are potential biomarkers that could indicate that the PD1-PDL1 interaction is playing an important role in a certain cancer, or that an individual could be responsive to therapies based on this interaction? One approach to finding effective biomarker signatures may be to screen the expression of a targeted set of genes related to cancer and immunity. The RT² Profiler Cancer Inflammation and Immunity Crosstalk qPCR array is one such panel, incorporating PD1 and PDL1 in addition to 82 other key genes involved in immunosuppression, inflammation, chemokine signaling and more. As PD1 and PDL1 are both conserved in mouse and rat, these species could also be good models to gain insight into the human biology.
Another key remaining question lies in the fact that human PD1 gene has 3 noncoding transcripts and 2 protein-coding transcripts – do the different coding transcripts have distinct impacts on how PD1-PDL1 interactions drive cancer, or could the noncoding transcripts have currently undiscovered roles? RNA sequencing could reveal the answers, and honing in on immunity genes with the QIAseq Targeted RNA Panel for immunity makes analysis quick and easy.
Researchers are also working on a host of other potential biomarkers, capturing information not just on T cell activity but also on metabolic and microbiome-related factors (6). To really combat this multi-factorial disease will require a well-timed and orchestrated combination of therapies, targeting multiple pathways and interactions – the race to the finish line continues! (3)
- 1. Mullard, A. (2016) Immuno-oncology drugs jostle for first-line setting. Nature Rev. Drug Discov. 15, 738. Link
- 2. Speiser, D, E. et al. (2016) Regulatory circuits of T cell function in cancer. Nature Rev. Immunol. 16, 599. Link
- 3. Palucka, A, K and Coussens, L.M. (2016) The basis of oncoimmunology. Cell 164, 1233. Link
- 4. Hoos, A. (2016) Development of immuno-oncology drugs – from CTLA4 to PD1 to the next generations. Nature Rev. Drug Discov. 15, 235. Link
- 5. Hughes, P, E. et al. (2016) Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol. 37, 462. Link
- 6. Kingwell, K. (2016) Biomarker search illuminates cancer immune biology. Nature Rev. Drug Disc. 15, 443. Link
- 7. Topalian, S, L. et al. (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nature Rev. Cancer 16, 275. Link