Transcriptomic profiling reveals M1-high tumour associated macrophages that orchestrate the adaptive Anti-tumour response in human lung cancer

Abstract

Tumour associated macrophages (TAMs) are thought to be biased towards an M2 phenotype, suppressing anti-tumour immune responses and thus therapies to eradicate macrophages have been proposed. However, current knowledge on TAMs in human cancer is based on a limited number of markers; their comprehensive M1 (anti-tumour) or M2 (pro-tumour) signatures, as well as their role in the anti-tumour immune response, have not yet been determined. Here, for the first time, we have generated transcriptomic data from TAMs isolated from human lung cancer, in comparison with non-tumour lung macrophages from the same patients. We found out that TAMs in lung cancer show a broad pro-tumour M2 signature, but that this signature is not associated with a weaker anti-immune response. However, it is the activation of an M1 signature in TAMs that determines whether TAMs can promote or not a strong anti-tumour immune response. We describe a novel set of M1high TAMs that simultaneously activate M1 and M2 signatures. M1high TAMs strongly activate antigen-presenting genes and express high levels of T-cell chemoattractants (CXCL9, 10 and 11), associating with a higher infiltration of anti-tumour CD8+ T-cells and a better clinical outcome. AIM2 and IL1beta levels are increased in M1high TAMs, indicating a direct involvement in pyroptosis and clearance of cancer cells. We provide a unique transcriptomic resource of TAMs in lung cancer and propose that TAMs can be used to improve immunotherapy due to a novel and pivotal role for M1high TAMs in orchestrating the immune adaptive anti-tumour responses.