Immune checkpoint inhibitors work by targeting proteins that keep immune responses in check, enabling T cells to kill cancer cells more effectively. Examples include those that target the programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1).
Although many of these agents are showing clinical promise for treating some types of cancer, results from trials so far show there is a huge inter-patient variability in response. To widen their benefits, we will need to develop a better understanding of some the key factors involved.
Two suspects that are likely to play important roles in this variable response are tumour immunogenicity and features of the tumour microenvironment, but the mechanisms aren’t currently well understood.
Now two new studies, both published in Nature, independently point the finger at increased transforming growth factor-β (TGF-β) signalling in the tumour microenvironment – implicating this in reduced immune surveillance and lack of response to treatment in two different metastatic solid tumour types:
- Tauriello et al. modelled metastatic colorectal tumours using compound genetic mouse models and organoid transplantation - finding that tumour immunogenicity involves stromal-derived TGF-β signalling in the tumour microenvironment, which seems to suppress T-cell differentiation and also to promote T-cell exclusion. Blocking TGF-β signalling (using galunisertib) reduces the growth of metastatic tumours – and the effect is synergistic in combination with anti-PD-L1.
- Mariathasan et al. looked at a large cohort of patients with metastatic urothelial carcinoma treated with anti-PD-L1 antibodies, finding that patients who did not respond had increased TGF-β signalling in fibroblasts within the tumour microenvironment accompanied by restricted T-cell infiltration. They showed that combining TGF-β blockade (anti-TGF-β) with immune checkpoint inhibition (anti-PD-L1) in mouse models of mammary carcinoma and colorectal cancer boosts the anti-tumour response.
The results of these studies suggest that inhibiting TGF-β signalling in cancers that are resistant to PD-L1 blockade may induce a more potent response, improving clinical outcomes in patients with advanced metastatic tumours that are growing in a TGF-β rich microenvironment. We look forward to more studies looking into this promising new combination.
Keeping the cancer-immune setpoint up-to-date
Are these new studies already referenced in the cancer-immune setpoint interactive figure? Where do you think they best fit? Please go to the framework and add your comments (n.b. you’ll need to be on a computer, rather than mobile!) – we need your help to keep on updating it as new data in these exciting field continues to be published.
To help get you started, please follow our a simple step-by-step guide in our ‘how to’ post.
- Harjes, V. Tear down this wall. Nature Reviews Cancer, published online 9 March 2018. doi:10.1038/nrc.2018.22
- Tauriello et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, p538-543 (2018). doi:10.1038/nature25492
- Mariathasan et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, p544-548 (2018). Doi:10.1038/nature25501