Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice

Multiple mechanisms of immunosuppression contribute to ability of cancer to avoid eradication by the immune system. Among these, expression of PD-L1 plays a key role in attenuating anti-tumour responses. PD-L1 can be adaptively expressed by tumour cells in response to inflammatory cytokines, thereby directly inhibiting T-cell mediated killing via binding its receptor PD-1. Therapeutic use of blocking antibodies has produced unparalleled, durable clinical responses, presumably by relieving suppression of primed T cells, with highest likelihood of response seen in patients whose tumours express PD-L1 prior to therapy. Unexpectedly PD-L1 expression by infiltrating myeloid and other immune cells is more prevalent and can be even more predictive of response, challenging the prevailing view that adaptive expression of PD-L1 by tumour cells is the sole source of PD-1 checkpoint control. The significance of PD-L1 expression in tumours has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Therefore, resolving functional contributions of immune versus tumour cell PD-L1 will be critical to the continued progress of cancer immunotherapy. Using genetic chimeras, we directly evaluate the relative roles of PD-L1 expression by the tumour and host’s immune cells, identifying their non-redundant roles in suppression of anti-tumour immune responses.