Targeting tumor-associated macrophages for cancer immunotherapy.

Tumor-associated macrophages (TAMs) are one of the most abundant immune components in the tumor microenvironment and play a plethora of roles in regulating tumorigenesis. Therefore, the therapeutic targeting of TAMs has emerged as a new paradigm for immunotherapy of cancer. Herein, the review summarizes the origin, polarization, and function of TAMs in the progression of malignant diseases. The understanding of such knowledge leads to several distinct therapeutic strategies to manipulate TAMs to battle cancer, which include those to reduce TAM abundance, such as depleting TAMs or inhibiting their recruitment and differentiation, and those to harness or boost the anti-tumor activities of TAMs such as blocking phagocytosis checkpoints, inducing antibody-dependent cellular phagocytosis, and reprogramming TAM polarization. In addition, modulation of TAMs may reshape the tumor microenvironment and therefore synergize with other cancer therapeutics. Therefore, the rational combination of TAM-targeting therapeutics with conventional therapies including radiotherapy, chemotherapy, and other immunotherapies is also reviewed. Overall, targeting TAMs presents itself as a promising strategy to add to the growing repertoire of treatment approaches in the fight against cancer, and it is hopeful that these approaches currently being pioneered will serve to vastly improve patient outcomes and quality of life.

Bioinformatics analysis of changes in genes associated with tumor-associated macrophages before and after neoadjuvant chemotherapy for breast cancer

Background and Aims: Breast cancer is the most prevalent malignancy in women worldwide, and chemotherapy is one of the most important treatment modalities for breast cancer. Recent studies have shown that chemotherapy may exert anti-tumor effects by enhancing anti-tumor immunity in the tumor microenvironment. Therefore, this study was conducted to identify the changes in tumor-associated macrophages (TAMs) and relevant genes before and after neoadjuvant chemotherapy (NAC) in breast cancer patients by bioinformatics analysis and to evaluate the effect of NAC on immune functions in breast cancer patients. Methods: Information searching was performed by entering "Breast Cancer", "TAMs", "Chemotherapy" and selecting the human breast cancer tissue in the GEO database, and the GSE134600 dataset was selected for analysis. Differentially expressed genes (DEGs) in tissue samples from breast cancer patients before and after NAC were screened by R package (limma function). GO function enrichment and KEGG pathway analysis were performed for all DRGs. The protein interaction network of DEGs was visualized by Cytoscape software, and hub genes were screened and 10 hub genes were analyzed for mutations by cBioPortal. Immune cell distribution and correlation in GSE134600 data were evaluated using the R package“CIBERSORT”. Results: A total of 751 DEGs (409 up-regulated and 342 down-regulated genes) were identified before and after NAC for breast cancer. The biology of DEGs was analyzed by GO enrichment for biological process（BP）, cellular component （CC）, and molecular function（MF）. In BP function, they were mainly enriched in type I interferon(IFN-I) signaling pathway/viral response and defense and viral life cycle;in CC function, they were mainly enriched in extrinsic components of cell membrane and cytoplasmic side of cell membrane;in MF function, they were mainly enriched in cytokine receptor binding, double-stranded RNA binding and lipopeptide binding. In the analysis of KEGG pathway enrichment, DEGs were mainly enriched in influenza A (H1N1), measles, hepatitis C, coronavirus disease COVID-19, NF-κB signaling pathway, EBV virus infection, NOD-like receptor signaling pathway, and amoeba disease signaling pathway. The top 10 hub genes with the highest degree of interaction with TAMs before and after NAC for breast cancer were screened by CytoHubba plug-in: IFIT1, ISG15, MX1, MX2, IRF7, RSAD2, IFIT3, IFI35, IFI6, and IFITM1. Multi-omics analysis revealed that IFIT1, MX1 and MX2 were mainly deletion mutations, IFIT1 mainly had deep gene deletion, while MX1 and MX2 were mainly associated with gene amplifications. The content of M0 macrophages, CD8+T cells and M2 macrophages in breast cancer tissues decreased after NAC, and M0 macrophages were positively correlated with memory B cells (r=0.64) and negatively correlated with unactivated CD4+ memory T cells (r=-0.66). Conclusion: The identified DEGs associated with TAMs in breast cancer patients before and after NAC are closely related to interferon signaling pathway, suggesting that interferon signaling pathway may play an important role by altering TAMs in NAC. Meanwhile, M0 macrophages are significantly altered before and after NAC, indicating that chemotherapy may regulate the immune response to tumor by changing the distribution of M0 macrophages and immune function. © 2022 Central South University. All right reserved.

Long-term benefit of lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma (MPM): final efficacy and translational data of the SAKK 17/16 study.

BACKGROUND: The SAKK 17/16 study showed promising efficacy data with lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma. Here, we evaluated long-term outcome and analyzed the impact of lurbinectedin monotherapy on the tumor microenvironment at the cellular and molecular level to predict outcomes. MATERIAL AND METHODS: Forty-two patients were treated with lurbinectedin in this single-arm study. Twenty-nine samples were available at baseline, and seven additional matched samples at day one of cycle two of treatment. Survival curves and rates between groups were compared using the log-rank test and Kaplan-Meier method. Statistical significance was set at P value <0.05. RESULTS: Updated median overall survival (OS) was slightly increased to 11.5 months [95% confidence interval (CI) 8.8-13.8 months]. Thirty-six patients (85%) had died. The OS rate at 12 and 18 months was 47% (95% CI 32.1% to 61.6%) and 31% (95% CI 17.8% to 45.0%), respectively. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months). No new safety signals were observed. Patients with lower frequencies of regulatory T cells, as well as lower tumor-associated macrophages (TAMs) at baseline, had a better OS. Comparing matched biopsies, a decrease of M2 macrophages was observed in five out of seven patients after exposure to lurbinectedin, and two out of four patients showed increased CD8+ T-cell infiltrates in tumor. DISCUSSION: Lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. According to our very small sample size, we hypothesize that baseline TAMs and regulatory T cells are associated with survival. Lurbinectedin seems to inhibit conversion of TAMs to M2 phenotype in humans.

Macrophage Polarity and Disease Control.

Macrophages are present in most human tissues and have very diverse functions. Activated macrophages are usually divided into two phenotypes, M1 macrophages and M2 macrophages, which are altered by various factors such as microorganisms, tissue microenvironment, and cytokine signals. Macrophage polarity is very important for infections, inflammatory diseases, and malignancies; its management can be key in the prevention and treatment of diseases. In this review, we assess the current state of knowledge on macrophage polarity and report on its prospects as a therapeutic target.

Potential of Ferritin-Based Platforms for Tumor Immunotherapy.

Ferritin is an iron storage protein that plays a key role in iron homeostasis and cellular antioxidant activity. Ferritin has many advantages as a tumor immunotherapy platform, including a small particle size that allows for penetration into tumor-draining lymph nodes or tumor tissue, a unique structure consisting of 24 self-assembled subunits, cavities that can encapsulate drugs, natural targeting functions, and a modifiable outer surface. In this review, we summarize related research applying ferritin as a tumor immune vaccine or a nanocarrier for immunomodulator drugs based on different targeting mechanisms (including dendritic cells, tumor-associated macrophages, tumor-associated fibroblasts, and tumor cells). In addition, a ferritin-based tumor vaccine expected to protect against a wide range of coronaviruses by targeting multiple variants of SARS-CoV-2 has entered phase I clinical trials, and its efficacy is described in this review. Although ferritin is already on the road to transformation, there are still many difficulties to overcome. Therefore, three barriers (drug loading, modification sites, and animal models) are also discussed in this paper. Notwithstanding, the ferritin-based nanoplatform has great potential for tumor immunotherapy, with greater possibility of clinical transformation.

Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer.

Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous "camouflage" in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages' ontogeny in macrophages' functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs' origins may help understand the classification of TAMs' population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.