PD-L1/PD-1 crosstalk in colorectal cancer: are we targeting the right cells?

Background: The analysis of tumour-infiltrating immune cells within patients' tumour samples in colorectal cancer (CRC) has become an independent predictor of patient survival. The tumour microenvironment and the immune checkpoints, such as PD-L1/PD-1, are relevant to the prognoses and also appear to be relevant for further CRC therapies. Methods: We analysed the presence and features of the infiltrated monocyte/macrophage and lymphocyte populations in both tumour and peritumour samples from patients with CRC (n = 15). Results: We detected a large number of CD14(+) monocytes/macrophages with an alternative phenotype (CD64(+)CD163(+)) and CD4(+) lymphocytes that infiltrated the tumour, but not the peritumour area. The monocytes/macrophages expressed PD-L1, whereas the lymphocytes were PD-1(+); however, we did not find high PD-L1 levels in the tumour cells. Coculture of circulating naive human monocytes/macrophages and lymphocytes with tumour cells from patients with proficient mismatch repair CRC induced both an alternative phenotype with higher expression of PD-L1 in CD14(+) cells and the T-cell exhaustion phenomenon. The addition of an alpha-PD-1 antibody restored lymphocyte proliferation. Conclusion: These results emphasise the interesting nature of immune checkpoint shifting therapies, which have potential clinical applications in the context of colorectal cancer.