Abstract:Successful antitumor immunity largely relies on efficient T cell priming by antigen-presenting cells (APCs); however, the capacity of APCs is found to be defective in many cancers. Metabolically reprogrammed cancer cells support the energetic and biosynthetic demands of their high proliferation rates by exploiting nutrients available in the tumor microenvironment (TME), which in turn limits proper metabolic reprogramming of APCs during recruitment, differentiation, activation and antigen presentation. Furtherm… Show more
“…Defective antigen presentation represents a major immune escape mechanism and also contributes to immunotherapy failure in malignancy 32 . Innate immune cells, including macrophages and DCs, are the major APCs as the first line defense against exotic organisms by up-taking exogenous antigens 33 . Novel subset-specific markers have recently been identified, including monocyte-derived STAB1 + TREM2 high LA-TAMs in gastric, colorectal, lung, and breast cancer 34 , 35 .…”
Background:
Lung cancer is associated with a high mortality rate and often complicated with malignant pleural effusion (MPE), which has a very poor clinical outcome with a short life expectancy. However, our understanding of cell-specific mechanisms underlying the pathobiology of pleural metastasis remains incomplete.
Methods:
We analyzed single-cell transcriptomes of cells in pleural effusion collected from patients with lung cancer and congestive heart failure (as a control), respectively. Soluble and complement factors were measured using a multiplex cytokine bead assay. The role of ferroptosis was evaluated by
GPX4
small interfering RNA (siRNA) transfection and overexpression.
Results:
We found that the mesothelial-mesenchymal transition (MesoMT) of the pleural mesothelial cells contributed to pleural metastasis, which was validated by lung cancer/mesothelial cell co-culture experiments. The ferroptosis resistance that protected cancer from death which was secondary to extracellular matrix detachment was critical for pleural metastasis. We found a universal presence of immune-suppressive lipid-associated tumor-associated macrophages (LA-TAMs) with complement cascade alteration in the MPE of the lung cancer patients. Specifically, upregulated complement factors were also found in the MPE, and C5 was associated with poor overall survival in the lung cancer patients with epidermal growth factor receptor mutation. Plasmacytoid dendritic cells (pDCs) exhibited a dysfunctional phenotype and pro-tumorigenic feature in the primary cancer. High expression of the gene set extracted from pDCs was associated with a poor prognosis in the lung cancer patients. Receptor-ligand interaction analysis revealed that the pleural metastatic niche was aggravated by cross-talk between mesothelial cells-cancer cells/immune cells via
TNC
and
ICAM1
.
Conclusions:
Taken together, our results highlight cell-specific mechanisms involved in the pathobiological development of pleural metastasis in lung cancer. These results provide a large-scale and high-dimensional characterization of the pleural microenvironment and offer a useful resource for the future development of therapeutic drugs in lung cancer.
“…Defective antigen presentation represents a major immune escape mechanism and also contributes to immunotherapy failure in malignancy 32 . Innate immune cells, including macrophages and DCs, are the major APCs as the first line defense against exotic organisms by up-taking exogenous antigens 33 . Novel subset-specific markers have recently been identified, including monocyte-derived STAB1 + TREM2 high LA-TAMs in gastric, colorectal, lung, and breast cancer 34 , 35 .…”
Background:
Lung cancer is associated with a high mortality rate and often complicated with malignant pleural effusion (MPE), which has a very poor clinical outcome with a short life expectancy. However, our understanding of cell-specific mechanisms underlying the pathobiology of pleural metastasis remains incomplete.
Methods:
We analyzed single-cell transcriptomes of cells in pleural effusion collected from patients with lung cancer and congestive heart failure (as a control), respectively. Soluble and complement factors were measured using a multiplex cytokine bead assay. The role of ferroptosis was evaluated by
GPX4
small interfering RNA (siRNA) transfection and overexpression.
Results:
We found that the mesothelial-mesenchymal transition (MesoMT) of the pleural mesothelial cells contributed to pleural metastasis, which was validated by lung cancer/mesothelial cell co-culture experiments. The ferroptosis resistance that protected cancer from death which was secondary to extracellular matrix detachment was critical for pleural metastasis. We found a universal presence of immune-suppressive lipid-associated tumor-associated macrophages (LA-TAMs) with complement cascade alteration in the MPE of the lung cancer patients. Specifically, upregulated complement factors were also found in the MPE, and C5 was associated with poor overall survival in the lung cancer patients with epidermal growth factor receptor mutation. Plasmacytoid dendritic cells (pDCs) exhibited a dysfunctional phenotype and pro-tumorigenic feature in the primary cancer. High expression of the gene set extracted from pDCs was associated with a poor prognosis in the lung cancer patients. Receptor-ligand interaction analysis revealed that the pleural metastatic niche was aggravated by cross-talk between mesothelial cells-cancer cells/immune cells via
TNC
and
ICAM1
.
Conclusions:
Taken together, our results highlight cell-specific mechanisms involved in the pathobiological development of pleural metastasis in lung cancer. These results provide a large-scale and high-dimensional characterization of the pleural microenvironment and offer a useful resource for the future development of therapeutic drugs in lung cancer.
“…For instance, metabolic modulators that enhance antigenpresenting cell activation or the vaccine-induced metabolic reprogramming of immune cells can enhance the immune response against tumor antigens. 99 Adoptive cell transfer therapies and metabolic interventions:…”
Section: Combination Therapies: Immunometabolism and Immunotherapymentioning
confidence: 99%
“…Combining vaccines with metabolic modulators can improve their efficacy by promoting immune cell activation and antigen presentation. For instance, metabolic modulators that enhance antigen‐presenting cell activation or the vaccine‐induced metabolic reprogramming of immune cells can enhance the immune response against tumor antigens 99 …”
Section: Strategies For Enhancing Immune Responsementioning
Immunometabolism, which studies cellular metabolism and immune cell function, is a possible cancer treatment. Metabolic pathways regulate immune cell activation, differentiation, and effector functions, crucial to tumor identification and elimination. Immune evasion and tumor growth can result from tumor microenvironment metabolic dysregulation. These metabolic pathways can boost antitumor immunity. This overview discusses immune cell metabolism, including glycolysis, oxidative phosphorylation, amino acid, and lipid metabolism. Amino acid and lipid metabolic manipulations may improve immune cell activity and antitumor immunity. Combination therapy using immunometabolism‐based strategies may enhance therapeutic efficacy. The complexity of the metabolic network, biomarker development, challenges, and future approaches are all covered, along with a summary of case studies demonstrating the effectiveness of immunometabolism‐based therapy. Metabolomics, stable isotope tracing, single‐cell analysis, and computational modeling are also reviewed for immunometabolism research. Personalized and combination treatments are considered. This review adds to immunometabolism expertise and sheds light on metabolic treatments' ability to boost cancer treatment immunological response. Also, in this review, we discussed the immune response in cancer treatment and altering metabolic pathways to increase the immune response against malignancies.
“…For the effects of inflammatory signals and antigen presentation in the TME, we refer the reader to recent reviews. 30 , 31 , 32 Figure 2 The immune composition of the T ME and the modalities sculpting it, a graphical representation of some of the functions and constituents of the TME. The composition of the TME is critical to tumour growth and response to therapy.…”
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