Malignant tumors are one of the major causes of human death, and the complexity of the tumor immune microenvironment (TIME) limits the effectiveness of various conventional therapies. Although various PD-1/PD-L1 immunosuppressants have achieved significant efficacy in some patients with advanced cancer, their therapeutic effects on most solid tumors are still limited. It may be related to the fact that solid tumor TIME has less T cell infiltration and is rich in immunosuppressive myeloid cells.
The CD47-Sirpα signaling pathway (also known as the "don't eat me" signal and phagocytic checkpoint) is a promising immunotherapy target on macrophages. Previous studies have shown that CD47 monoclonal antibody-mediated phagocytosis requires the phagocytosis signal SLAMF7, which is not expressed by most solid tumors (Chen J., et al. Nature, 2017). Recent clinical trials have shown that CD47 blockers have good effects on several blood tumors, but their therapeutic effects on solid tumors are very limited. These all suggest that the accumulation of dysfunctional macrophages in TIME may be one of the main reasons for immune evasion and unresponsiveness to immunotherapy in solid tumors. Targeting myeloid cells through CD47 blockade may not be the best strategy for immunotherapy of solid tumors. Therefore, the immunosuppressive mechanism of myeloid cells in TIME needs further study.
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Recently, researchers from Sun Yat-sen School of Medicine at Sun Yat-sen University in China published a research paper titled "Sirpα on tumor-associated myeloid cells restrains anti-tumor immunity in colorectal cancer independent of its interaction with CD47" in Nature Cancer. This study first performed single-cell transcriptome sequencing on colorectal cancer patients and found that tumor-associated macrophages (TAMs) and granulocytic myeloid-derived suppressor cells (gMDSCs) were significantly enriched in tumor tissues and showed the strongest immunosuppressive. At the same time, the immunoreceptor SIRPA containing the immunoreceptor tyrosine inhibitory motif (ITIM) is highly expressed. Furthermore, this finding was confirmed in public data.
To further explore the impact of immunosuppressive receptors such as SIRPA on tumors, the research team used CRISPR-Cas9 technology to establish multiple gene knockout mice (Sirpα KO, Clec4a KO and Siglec-E KO). Compared with wild-type (WT) mice, the tumors inoculated in Clec4a KO and Siglec-E KO mice were similar in size to those in WT mice. However, tumor progression was significantly inhibited in both the subcutaneous and spontaneous colorectal cancer models of Sirpα KO mice, and the survival rate of mice was significantly improved. At the same time, tumor progression was also significantly inhibited in liver and lung cancer models of Sirpα KO mice. Analysis of clinical data sets found that the expression level of Sirpα is negatively correlated with the prognosis of patients with various solid tumors. These results indicate that Sirpα is closely related to tumor development, and loss of Sirpα significantly inhibits the progression of a variety of solid tumors.
Figure 1. Sirpα deficiency prohibits spontaneous colon cancer development. (Huang C, et al. 2024)
Interestingly, by knocking out the CD47 molecule on tumor cells and conducting experiments using CD47 monoclonal antibodies and Sirpαa-ED-Fc fusion protein, researchers have confirmed that the immunosuppressive receptor Sirpα plays a role in promoting tumor immune evasion independent of its interaction with the classic ligand CD47. Further single-cell transcriptome sequencing analysis and experimental verification of the intestinal tumor tissue of the mouse orthotopic colorectal cancer model found that Sirpα knockout can transform TAMs and gMDSCs into TAM_Ccl8hi and gMDSC_H2-Q10hi subpopulations with stronger antigen presentation ability, phagocytosis ability, inflammatory response ability and chemotaxis. It can also promote the activation and proliferation of T cells, thereby reshaping TIME to exhibit stronger anti-tumor effects.
In vitro experiments have shown that macrophages in Sirpα knockout mice can promote T cell recruitment and exert anti-tumor immunity through Syk/Btk kinase-dependent Ccl8 secretion. In addition, the researchers also found that the combination treatment of Sirpα knockout and anti-PD-L1 can show better tumor suppression effect.
In summary, targeting Sirpα can simultaneously regulate innate immunity and adaptive immunity, reshape the tumor immune microenvironment and prevent the progression of solid tumors. Blocking Sirpα is expected to become a new target for solid tumor immunotherapy and overcome the dilemma of solid tumor immunotherapy resistance.
Reference
Huang C, et al. Sirpα on tumor-associated myeloid cells restrains antitumor immunity in colorectal cancer independent of its interaction with CD47. Nature Cancer, 2024: 1-17.