Upregulation of PD-L1 as a putative mechanism of resistance to CD47 inhibition in non-small cell lung cancer

Abstract

CD47 is a "dont eat me" signal that suppresses macrophage-mediated phagocytosis. Its upregulation in lung and other cancers facilitates tumour immune escape, making CD47 a promising immunotherapeutic target. Studies have demonstrated anti-tumour efficacy of CD47 blockade in preclinical lung cancer models, but monoclonal antibodies targeting CD47 have had limited efficacy as monotherapy in solid tumour patients to date. This discrepancy may in part reflect the use of human tumour xenografts in mice that do not have fully-functioning immune systems in preclinical efficacy studies. Thus, understanding tumour responses to CD47 inhibition using immune competent lung cancer models is needed to inform strategies to harness its therapeutic potential. Here, we characterized the effects of CD47 knockout (KO) on tumour growth and immune responses in two syngeneic, orthotopic murine lung cancer models, LLC-Luc (LLC) and CMT167 (CMT). As expected, CD47 KO impaired the fitness of LLC and CMT cells in vivo. Mice with CD47-deficient tumours exhibited prolonged survival and increased infiltration of anti-tumour leukocytes. However, although CD47 KO impaired lung tumour growth in syngeneic mice, KO tumours were ultimately lethal. Immunophenotyping revealed an increased prevalence of PD-L1+ cells in CD47-deficient tumours, nominating PD-L1-mediated suppression of tumour immunity as an acquired mechanism of resistance to CD47 blockade. Concordantly, dual inhibition of CD47 and PD-L1 extended the survival of CMT tumour-bearing mice compared to inhibition of either alone. These findings suggest that PD-L1 blockade could be leveraged to overcome resistance and potentiate the efficacy of CD47-targeted immunotherapy in lung cancer.