M1^hottumor-associated macrophages boost tissue-resident memory T cells infiltration and survival in human lung cancer

Abstract

BackgroundThe role of tumor-associated macrophages (TAMs) in determining the outcome between the antitumor effects of the adaptive immune system and the tumor’s anti-immunity stratagems, is controversial. Macrophages modulate their activities and phenotypes by integration of signals in the tumor microenvironment. Depending on how macrophages are activated, they may adopt so-called M1-like, antitumor or M2-like, protumor profiles. In many solid tumors, a dominance of M2-like macrophages is associated with poor outcomes but in some tumor types, strong M1-like profiles are linked to better outcomes. We aimed to investigate the interrelationship of these TAM populations to establish how they modulate the efficacy of the adaptive immune system in early lung cancer.MethodsMacrophages from matched lung (non-tumor-associated macrophages (NTAMs)) and tumor samples (TAMs) from resected lung cancers were assessed by bulk and single-cell transcriptomic analysis. Protein expression of genes characteristic of M1-like (chemokine (C-X-C motif) ligand 9) or M2-like (matrix metallopeptidase 12) 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 tumors and survival data from an independent cohort of 393 patients with lung cancer.ResultsTAMs 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-sequencing 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 tumors that was in turn linked to better survival. Our data suggest 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.ConclusionsWe 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 tumor-infiltrate and better outcomes. Thus, therapeutic approaches to re-program TAMs to an M1hot phenotype are likely to augment the adaptive antitumor responses.

CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer

“…Interestingly, enrichment of a CD8 Trm signature was found in NSCLC patient samples containing higher levels of CXCL9 when compared with CXCL9 negative tumors. 30 This study suggested that M1 hot TAMs provide fatty acids to CD8+C-D103+Trm cells within the TME, a known mechanism for supporting peripheral CD8 T cell effector functions. 48 Further, CXCL9/10 expressing macrophages have been shown to directly promote effector CD8 T cell function.…”

“… 25 A recent transcriptomic profiling study of TAMs from lung cancer patients also identified variable expression of inflammatory-macrophage-associated genes, most notably Cxcl9, Cxcl10 and Stat1 ascribed to an ‘M1 hot ’ phenotype. 30 Genes associated with this M1 hot state, including Cxcl9, correlated with increased survival and a higher density of intratumorous CD8 T cells indicating that human myeloid populations bearing a highly similar transcriptional state to murine Cxcl9 expressing-TAMs correlate with survival and accumulation of CD8 T cells in human cancer.…”

Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

“…Nevertheless, our results demonstrate, at least in part, a potent role for M1 macrophages in shaping the immunostimulatory TME observed in cases with LG tumor budding. In a recent report by Garrido-Martin et al, the authors showed through single-cell transcriptomics in lung cancer, that while a majority of TAMs exhibited M2-like properties, 25% of cases exhibited macrophages with M1-like features, which were implicated in recruiting T cells via CXCL9 [ 54 ]. In our study, LS tumor budding cases from TCGA demonstrated significantly higher CXCL9 expression compared to HS patients suggesting that M1 macrophages are a key cellular source of CXCL9 in PDAC.…”

Legend of the Sentinels: Development of Lung Resident Memory T Cells and Their Roles in Diseases

“…Another study indicated that lung T RM cells were programmed to express IFITM3, which can protect them from secondary infection and improve survival ( 48 ). Except for cytokines and surface molecules, M1 hot tumor-associated macrophages can also contribute to the maintenance of lung T RM cells in tumor, possibly due to reduction in nutrition competition ( 49 ). In comparison with other tissue T RM cells that may persist for a long time or even a lifetime, lung T RM cells gradually disappear 4–5 months after infection.…”