The authors have previously shown a correlation between a decrease in a population of CD4+Foxp3‑PD‑1hi T cells (4PD1hi) in the tumours of B16‑bearing mice, and therapeutic efficacy. Amongst the antibody therapies tested, CTLA‑4 blockade induced the most number of intra-tumour 4PD1hi cells when combined with the virus-based anti-melanoma vaccine (VRP‑TRP2). αCTLA‑4 was also the least effective in controlling tumour growth. (Avogadri et al. 2014. Cancer Immunol. Res. 2, 448-458.)
To determine whether 4PD1hi cells contribute to tumour immune evasion in cancer patients, the authors monitored this cell subset in patients treated with nivolumab or pembrolizumab (αPD‑1) and show that they reduce peripheral 4PD1hi cells. This effect was abrogated when combined with ipilimumab (αCTLA4).
Using the B‑16 melanoma mouse model, the authors show that the number of circulating 4PD1hi cells increases after αCTLA‑4 monotherapy in a dose dependent manner. Triple treatment of tumour bearing mice with VRP‑TRP2, αCTLA‑4 and αPD‑1 was superior in reducing tumour growth when compared to the individual antibodies, with or without the vaccine. This response correlated with reduced intra-tumour 4PD1hi cells. Further, whilst the combination of αPD‑1 and VRP‑TRP2 prevented the increase in 4PD1hi cells, it promoted intra-tumour CD4+Foxp3+ regulatory T cells (Tregs). The increase in Tregs was abrogated with the triple therapy.
Using transcriptional profiling, the RNA gene expression profiles of human and mouse 4PD1hi, 4PD1neg and Treg cells were analysed and compared. Analysis of variably expressed genes show that 4PD1hi cells show extensive overlap with the gene signatures of follicular helper T cell (TFH).
A significant proportion of cancer patients do not respond to checkpoint inhibitors. Measurement of circulating 4PD1hi cells in patients receiving check point inhibitors may act as valid biomarkers that allow for better stratification and design of combinatorial therapy.