M1hot tumour associated macrophages are positively associated with tissue-resident memory T cell responses and survival outcomes in human lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116948 | GEO | 2020/07/29
REPOSITORIES: GEO
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Project description:Tumour-associated macrophages (TAMs) are classified as M1 (“anti-tumour”) and M2 (“pro-tumour”), but their balance has not yet been accurately established in human cancer tissue. Here, we present bulk and single-cell transcriptomic data from human TAMs isolated from lung cancer compared with autologous non-tumour involved lung tissue macrophages (N-TAM). TAMs have a profoundly different transcriptomic profile from N-TAMs and displayed a broad M2 pro-tumour signature that was homogeneous across all the lung cancer patients studied. However, in some tumours, we found TAM populations that simultaneously displayed strong M1 gene expression pattern. These M1hot TAMs appeared to contribute to effective anti-tumour immunity via expression of T cell chemo-attractants (CXCL9, 10 and 11). We found that M1hot TAMs expressed low levels of FABP3, 4 and 5, take up less fatty acids and showed “metabolic generosity” to tissue resident memory T cells (TRM) by allowing them access to this essential nutrient resource that is required for their maintenance. Importantly, tumours harbouring M1hot TAMs were highly enriched for TRM cells and were also associated with improved overall survival outcomes. Our findings suggest that immunotherapeutic approaches aimed at inducing the expression of M1hot program in TAMs rather than generically eliminating all TAMs are likely to be beneficial.
2020-07-29 | GSE116946 | GEO
Project description:Tumour-associated macrophages (TAMs) are classified as M1 (“anti-tumour”) and M2 (“pro-tumour”), but their balance has not yet been accurately established in human cancer tissue. Here, we present bulk and single-cell transcriptomic data from human TAMs isolated from lung cancer compared with autologous non-tumour involved lung tissue macrophages (N-TAM). TAMs have a profoundly different transcriptomic profile from N-TAMs and displayed a broad M2 pro-tumour signature that was homogeneous across all the lung cancer patients studied. However, in some tumours, we found TAM populations that simultaneously displayed strong M1 gene expression pattern. These M1hot TAMs appeared to contribute to effective anti-tumour immunity via expression of T cell chemo-attractants (CXCL9, 10 and 11). We found that M1hot TAMs expressed low levels of FABP3, 4 and 5, take up less fatty acids and showed “metabolic generosity” to tissue resident memory T cells (TRM) by allowing them access to this essential nutrient resource that is required for their maintenance. Importantly, tumours harbouring M1hot TAMs were highly enriched for TRM cells and were also associated with improved overall survival outcomes. Our findings suggest that immunotherapeutic approaches aimed at inducing the expression of M1hot program in TAMs rather than generically eliminating all TAMs are likely to be beneficial.
2020-07-29 | GSE116947 | GEO
Project description:M1hot tumour associated macrophages are positively associated with tissue-resident memory T cell responses and survival outcomes in human lung cancer
| PRJNA480668 | ENA
Project description:M1hot tumour associated macrophages are positively associated with tissue-resident memory T cell responses and survival outcomes in human lung cancer (bulk).
| PRJNA480670 | ENA
Project description:M1hot tumour associated macrophages are positively associated with tissue-resident memory T cell responses and survival outcomes in human lung cancer (single cells).
| PRJNA480671 | ENA
Project description:The 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. Macrophages 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. 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-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. 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 tumor-infiltrate and better outcomes. Thus, therapeutic approaches to re-program TAMs to an M1hot phenotype are likely to augment the adaptive antitumor responses.
| S-EPMC7375465 | biostudies-literature
Project description:Aside from centrally induced trained immunity in the bone marrow (BM) and peripheral blood by parenteral vaccination or infection, evidence indicates that mucosal-resident innate immune memory can develop via a local inflammatory pathway following mucosal exposure. However, whether mucosal-resident innate memory results from integrating distally generated immunological signals following parenteral vaccination/infection is unclear. Here we show that subcutaneous Bacillus Calmette-Guérin (BCG) vaccination can induce memory alveolar macrophages (AMs) and trained immunity in the lung. Although parenteral BCG vaccination trains BM progenitors and circulating monocytes, induction of memory AMs is independent of circulating monocytes. Rather, parenteral BCG vaccination, via mycobacterial dissemination, causes a time-dependent alteration in the intestinal microbiome, barrier function and microbial metabolites, and subsequent changes in circulating and lung metabolites, leading to the induction of memory macrophages and trained immunity in the lung. These data identify an intestinal microbiota-mediated pathway for innate immune memory development at distal mucosal tissues and have implications for the development of next-generation vaccine strategies against respiratory pathogens.
| S-EPMC9747617 | biostudies-literature
Project description:Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.
| S-EPMC8140108 | biostudies-literature
Project description:Tissue resident memory CD8 T cells (TRM) serve as potent local sentinels and contribute significantly to protective immunity against intracellular mucosal pathogens. While the molecular and transcriptional underpinnings of TRM differentiation are emerging, how TRM establishment is regulated by other leukocytes in vivo is largely unclear. Here, we observed that expression of PPAR-γ in the myeloid compartment was a negative regulator of CD8 TRM establishment following influenza virus infection. Interestingly, myeloid deficiency of PPAR-γ resulted in selective impairment of the tissue-resident alveolar macrophage (AM) compartment during primary influenza infection, suggesting that AM are likely negative regulators of CD8 TRM differentiation. Indeed, influenza-specific CD8 TRM cell numbers were increased following early, but not late ablation of AM using the CD169-DTR model. Importantly, these findings were specific to the parenchyma of infected tissue as circulating memory T cell frequencies in lung and TCM and TEM in spleen were largely unaltered following macrophage ablation. Further, the magnitude of the effector response could not explain these observations. These data indicate local regulation of pulmonary TRM differentiation is alveolar macrophage dependent. These, findings could aid in vaccine design aimed at increasing TRM density to enhance protective immunity, or deflating their numbers in conditions where they cause overt or veiled chronic pathologies.
| S-EPMC6797929 | biostudies-literature
Project description:Previous pneumococcal experience establishes lung-resident IL-17A-producing CD4+ memory TRM cells that accelerate neutrophil recruitment against heterotypic pneumococci. Herein, we unravel a novel crosstalk between CD4+ TRM cells and lung epithelial cells underlying this protective immunity. Depletion of CD4+ cells in pneumococcus-experienced mice diminished CXCL5 (but not CXCL1 or CXCL2) and downstream neutrophil accumulation in the lungs. Epithelial cells from experienced lungs exhibited elevated mRNA for CXCL5 but not other epithelial products such as GM-CSF or CCL20, suggesting a skewing by CD4+ TRM cells. Genome-wide expression analyses revealed a significant remodeling of the epithelial transcriptome of infected lungs due to infection history, ~80% of which was CD4+ cell-dependent. The CD4+ TRM cell product IL-17A stabilized CXCL5 but not GM-CSF or CCL20 mRNA in cultured lung epithelial cells, implicating posttranscriptional regulation as a mechanism for altered epithelial responses. These results suggest that epithelial cells in experienced lungs are effectively different, owing to their communication with TRM cells. Our study highlights the role of tissue-resident adaptive immune cells in fine-tuning epithelial functions to hasten innate immune responses and optimize defense in experienced lungs, a concept that may apply broadly to mucosal immunology.
| S-EPMC7044037 | biostudies-literature