M1(hot)tumor-associated macrophages boost tissue-resident memory T cells infiltration and survival in human lung cancer

Background: the role of Tumour-Associated Macrophages (TAMs) in determining the outcome between the anti-tumour effects of the adaptive immune system and the tumour’s anti-immunity stratagems, is controversial. Macrophages modulate their activities and phenotypes by integration of signals in the tumour micro-environment. Depending on how macrophages are activated, they may adopt so-called M1-like, anti-tumour or M2-like, pro-tumour profiles. In many solid tumours, a dominance of M2-like macrophages is associated with poor outcomes but in some tumour types, strong M1-like profiles are linked to better outcomes. We aimed to investigate the inter-relationship of these TAM populations to establish how they modulate the efficacy of the adaptive immune system in early lung cancer.Methods: macrophages from matched lung (NTAMs) and tumour samples (TAMs) from resected lung cancers were assessed by bulk and single-cell transcriptomic analysis. Protein expression of genes characteristic of M1-like (CXCL9) or M2-like (MMP12) functions was confirmed by confocal microscopy. Immunohistochemistry related the distribution of TAM transcriptomic signatures to density of CD8+ tissue-resident memory T cells (TRM) in tumours and survival data from an independent cohort of 393 lung cancer patientsResults: TAMs have significantly different transcriptomic profiles from NTAMs with >1000 differentially expressed genes. TAMs displayed a strong M2-like signature with no significant variation between patients. However, single-cell RNA-seq supported by immuno-stained cells revealed that additionally, in 25% of patients the M2-like TAMs also co-expressed a strong/hot M1-like signature (M1hot). Importantly, there was a strong association between the density of M1hot TAMs and TRM cells in tumours that was in turn linked to better survival. Our data suggests a mechanism by which M1hot TAMs may recruit TRM cells via CXCL9 expression and sustain them by making available more of the essential fatty acids on which TRM depend.Conclusions: we showed that in early lung cancer, expression of M1-like and M2-like gene signatures are not mutually exclusive since the same TAMs can simultaneously display both gene-expression profiles. The presence of M1hot TAMs was associated with a strong TRM tumour-infiltrate and better outcomes. Thus, therapeutic approaches to re-program TAMs to an M1hot phenotype are likely to augment the adaptive anti-tumour responses