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Cancer creates an environment of constant antigen exposure and inflammation. In this setting, T cells transform into a differentiation state that has been termed T cell exhaustion, which is characterised by upregulation of inhibitory receptors, like TIM-3 and PD-1, resulting in loss of effector function. The discovery of receptor-mediated immune checkpoints, which prevent uncontrolled T cell reactions, led to the development of a new class of antibodies termed checkpoint inhibitors, bringing exhaustion phenomena to the forefront of tumour research. Data on the efficacy of checkpoint inhibitors in pancreatic cancer are still sparse; however, preliminary results indicate limited efficacy as single agents. In order to increase therapeutic efficacy, knowledge on T cell exhaustion mechanisms in pancreatic cancer is mandatory.
Recently, sophisticated models have confirmed the notion that components of the tumour stroma regulate functionality of intratumoral T cells. Whereas cytotoxic CD8+ effector T cells mark the centrepiece of a successful tumour immune response, M2 tumour-associated macrophages and myeloid derived suppressor cells are immunosuppressive. The stromal depletion hypothesis suggested that efficacy of chemotherapeutic drugs is increased by inhibition of stromal signalling cascades.1 However, a number of unexpected results has been reported recently, and the precise role of mesenchymal constituents of pancreatic stroma remains to be defined. Depletion of cancer-associated fibroblasts has been shown to accelerate tumour growth, and deletion of sonic hedgehog, a soluble ligand driving the formation of fibroblast-rich desmoplastic stroma, increased proliferation and dedifferentiation of tumours.2 Reduced myofibroblast frequency in patients with pancreatic cancer correlated with shorter survival.3 These data have questioned the belief that stromal elements of pancreatic cancer are tumour promoting. Instead, a more refined paradigm is evolving.
Here, Zhang et al use CD11b-DTR mice to investigate the effect of myeloid cell depletion on tumour progression by transplanting primary mouse pancreatic cancer cells into CD11b-DTR mice. Furthermore, the iKras mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b+ cells were depleted by diphtheria toxin treatment during tumour initiation or in established tumours. Authors show that CD11b+ myeloid cells regulate CD8+T cell exhaustion, and propose that the main mechanism is upregulation of PD-L1 on tumour cells, modulated by the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signalling pathway.
In a transwell approach, it was demonstrated that myeloid cells are able to induce the expression of Pdcdlg1 (encoding for PD-L1) in the tumour microenvironment. CD8+ T cells expressed markers of exhaustion such as Pdcd-1 and Ctla4; depletion of myeloid cells reduced the expression of exhaustion markers of CD8+ T cells and reinstalled CD8+T cell anti-tumour efficacy.
Co-culture of human pancreatic ductal adenocarcinoma (PDA) cell lines with BM-derived cells led to an increase in EGFR phosphorylation in tumour cells, indicating activation of EGFR signalling. In non-small cell lung cancer, EGFR signalling has been reported to induce PD-L1 expression before.4 However, this effect has not been described for pancreatic cancer so far. Authors conclude that myeloid cells are required for sustained MAPK signalling in pancreatic epithelial cells. Accordingly, treatment with mitogen-activated protein kinase (MEK) inhibitors lowered intratumoral expression of PD-L1 and rendered the tumour susceptible to PD-1 blockade.
Zhang et al suggest that CD11b+ myeloid cells protect tumour cell viability by blocking CD8+ T cell-mediated anti-tumour responses in pancreatic cancer. Mechanistically, CD11b+ cells employ EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells to induce a state of dysfunction/exhaustion in CD8+ T cells. These findings are important for our understanding how immune cell populations within the tumour microenvironment transmit activating versus exhausting signals between themselves. It will be interesting to see how other important cell populations, such as regulatory T cells, can be included into this emerging paradigm.
Editorial to: Zhang et al. Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immune-suppressive environment in pancreatic cancer.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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