Single-cell Sequencing Technology Facilitates Identification of Macrophage Immunotherapeutic Targets

Single-cell sequencing technology is gradually changing researchers' understanding of the tumor microenvironment (TME), especially the role of TAMs in it with its impact on immunotherapy. Here, Creative Biolabs gives some examples of studies exploring TAMs-related targets in immunotherapy through the use of single-cell technologies.

TAMs-related Targets in Immunotherapy

With the continuous advancement of science and technology, single-cell perspective analysis has provided researchers with the possibility to gain a deeper understanding of cellular heterogeneity in the tumor microenvironment. Based on single-cell technology, subpopulations of TAM and their respective functions have been revealed, helping researchers to find new immunotherapeutic targets.

• In 2023, researchers have found that TGFBI is mainly expressed and secreted by TAMs by technical means such as single-cell RNA sequencing. This study suggests that TGFBI is a key molecule connecting macrophages and pancreatic cancer cells, and targeting TGFBI may become a new strategy for pancreatic cancer treatment.
  • TGFBI can promote macrophage polarization toward M2 type and act as a secreted factor to directly promote the proliferation of pancreatic cancer cells.
  • In a mouse model, targeted knockdown of TGFBI expression on macrophages could inhibit tumor growth and improve the tumor microenvironment.
• In 2023, one study provided a new target for intervention through single-cell sequencing technology, flow cytometry, and others, namely revealing that ACOD1 can be a potential target for immuno-oncology drugs. This study confirms that IRG1-deficient macrophages represent an effective cell therapy strategy for cancer treatment, even in pancreatic tumors that are resistant to T-cell-based immunotherapy.
• In 2022, a study combining single-cell sequencing with CyTOF mass spectrometry and flow cytometry dissected the immune microenvironment of HCC at multiple levels from the single-cell transcriptome and proteome, analyzed in depth the functional manifestations of the target subpopulation of PPT1+ macrophages, and found that PPT1+ macrophage infiltration was associated with poor prognosis in HCC patients, and that targeting PPT1 might enhance the efficacy of HCC immunotherapy.
• In 2021, a study showed that the expression patterns of TMEM119 and MHC-II can be used to differentiate the origin and activation status of TAMs and further identified SPI1 as a key regulator and potential immunotherapeutic target important for TAM maturation and polarization in glioblastoma.

Perspectives on Macrophage-related Research

Single-cell technology reveals molecules that exist on the surface of macrophages and have important regulatory functions, and then using these targets can be used to design antibody drugs that target macrophages. On this basis, scientists can use antibody drugs to block the immunosuppressive effects of TAM in the tumor environment.

Cell editing technologies such as CRISPR can be used to screen for molecules that are important for macrophage polarization, and targeting these molecules to achieve the transformation of cells that are inhibitory to tumor growth from TAM that promote tumor growth will have a profound impact on immunotherapeutic strategies for TAM reprogramming.

By targeting TAM-associated targets for immunotherapy, better treatment outcomes can be achieved for tumor patients. However, it still needs to be explored in depth, and more advanced techniques and experiments are needed to further determine the potential utility of these strategies and the challenges they may face.

References

1. Zhou, Jing, et al. "A novel role of TGFBI in macrophage polarization and macrophage-induced pancreatic cancer growth and therapeutic resistance." Cancer letters 578 (2023): 216457.
2. Chen, Yu-Jia, et al. "Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy." Science Advances 9.17 (2023): eadg0654.
3. Weng, Jialei, et al. "Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma." Journal for Immunotherapy of Cancer 11.6 (2023).
4. Cui, Xiaoteng, et al. "Single-cell transcriptomics of glioblastoma reveals a unique tumor microenvironment and potential immunotherapeutic target against tumor-associated macrophage." Frontiers in Oncology 11 (2021): 710695.