CD163(+) M2-type tumor-associated macrophage support the suppression of tumor-infiltrating T cells in osteosarcoma
Qinglin Han1, Hongguang Shi1, Fan Liu1
1Surgical Research Laboratory, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
Abstract:
Osteosarcoma is one of the most common childhood cancers with high numbers of cancer-related deaths. Progress in conventional therapies is showing limited improvement. An adaptive T cell-based immunotherapy represents a promising new therapeutic option, but to improve its efficacy, regulatory mechanisms in osteosarcoma need further elucidation. Here, to evaluate the regulatory effect of tumor microenvironment of T cells in osteosarcoma, we examined the peripheral blood (PB) and tumor infiltrating (TI) T cells, and their correlations with PB and tumor immune characteristics. We found that TI T cells contained significantly higher levels of TIM-3(+)PD-1(-) and TIM-3(+)PD-1(+) cells than their PB counterparts. Similar to that in chronic HIV and HCV infections, these TIM-3(+)PD-1(-) and TIM-3(+)PD-1(+) T cells presented reduced proliferation and proinflammatory cytokine secretion in response to stimulation. Presence of M2-type (CD163(+)) macrophages exacerbated T cell immunosuppression, since frequencies of CD163(+) tumor-associated macrophages were directly correlated with the frequencies of suppressed TIM-3(+)PD-1(+) T cells. Moreover, depletion of CD163(+) macrophages significantly improved T cell proliferation and proinflammatory cytokine production. Overall, our data presented an intratumoral T cell-specific immunosuppression that was amplified by M2-type tumor-associated macrophages.
Insights
Tumor-infiltrating T cells in osteosarcoma exhibit suppressed function, exacerbated by M2 macrophages. Depleting these macrophages enhances T cell activity, offering a potential immunotherapy target for this childhood cancer.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Osteosarcoma is a prevalent childhood cancer with poor outcomes.
- Conventional therapies offer limited improvement, highlighting the need for novel treatments.
- T cell-based immunotherapy shows promise, but its efficacy is hindered by tumor microenvironment factors.
Purpose of the Study:
- To investigate the regulatory mechanisms of T cells within the osteosarcoma tumor microenvironment.
- To evaluate the impact of tumor-associated macrophages on T cell function in osteosarcoma.
Main Methods:
- Comparative analysis of peripheral blood (PB) and tumor-infiltrating (TI) T cells.
- Assessment of T cell markers (TIM-3, PD-1) and cytokine secretion.
- Correlation analysis between T cell function, macrophage phenotypes (M2/CD163+), and clinical characteristics.
- Experimental depletion of CD163+ macrophages to assess functional recovery of T cells.
Main Results:
- TI T cells showed higher frequencies of TIM-3(+)PD-1(-) and TIM-3(+)PD-1(+) cells compared to PB T cells.
- These T cells exhibited diminished proliferation and proinflammatory cytokine production, similar to chronic infections.
- M2-type (CD163+) macrophages were associated with increased T cell immunosuppression.
- Depletion of CD163+ macrophages led to improved T cell proliferation and cytokine secretion.
Conclusions:
- Osteosarcoma features intratumoral T cell-specific immunosuppression.
- M2-type tumor-associated macrophages significantly amplify this T cell suppression.
- Targeting M2 macrophages may enhance T cell-based immunotherapy efficacy in osteosarcoma.
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