CD163+ M2-type tumor-associated macrophage support the suppression of tumor-infiltrating T cells in osteosarcoma
Introduction
Osteosarcoma is one of the most common childhood cancers with the second highest number of cancer-related deaths in pediatric patients [1], [2]. The five-year survival rate is only 65% on average, and only 15% to 30% for metastasized tumors. Currently, treatment options are limited to multi-agent chemotherapy and surgical resections, which could present significantly high toxicity and risk of incomplete tumor removal [3]. Recent developments in current treatments have shown only incremental improvements on patient survival [4], [5]. Therefore, the potential application of adaptive T cell immunotherapy, which utilizes tumor antigen-specific T cells, has been investigated [6], [7], [8].
Although T cell immunotherapies have shown great promise for B cell lymphomas, many challenges remain in adopting the same strategy for treating osteosarcoma, due to the low expression of recurrent targetable tumor-specific mutations and the immunosuppressive environment in solid tumors [9]. Expression of programmed death ligand 1 (PD-L1), a ligand for the apoptosis-inducing inhibitory TNFR family molecule PD-1 expressed on activated T cells, was observed in metastatic osteosarcoma tumors [10]. T cell immunoglobulin- and mucin-domain containing molecule 3 (TIM-3), a marker of exhausted T cells in chronic infections, was also observed in osteosarcoma tumors [11]. IL-10-expressing M2-type tumor-associated macrophages (TAMs) were observed in osteosarcoma [12]. These studies suggest that immunosuppression may play a role in the development of osteosarcoma, but very little is understood on the regulation of T cell responses in osteosarcoma patients. It is unknown whether osteosarcoma is more likely to develop and propagate in patients with immune-compromised and/or immune-suppressed individuals, or the tumor microenvironment could actively inhibit inflammation. A previous study in HIV/AIDS patients demonstrated an elevated risk and severity of developing osteosarcoma in these patients, demonstrating the link between weak immune responses and osteosarcoma development [13]. But the effect of intratumoral PD-1 and Tim-3 on tumor T cells in osteosarcoma has not been closely examined.
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 T cell receptor (TCR) stimulation. Presence of M2-type (CD163+) macrophages exacerbated T cell immunosuppression, since 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 TAMs.
Section snippets
Patient information and sample collection
The study was approved by the institutional review board of The Affiliated Hospital of Nantong University. Written informed consent was obtained from all participants over the age of 18, and from all guardians of the participants who are under 18. The study population consisted of 16 primary osteosarcoma patients with localized tumor at various locations, who later underwent tumor resection. Osteosarcoma was diagnosed through histological examinations. Patients with other severe and potentially
Higher frequencies of TIM-3+ PD-1− and TIM-3+ PD-1+ T cells in TI cells compared to PB cells
TIM-3 and PD-1 are negative regulators of IFN-γ production in T cells and could promote apoptosis [14], [15], [16], [17]. Overrepresentations of Tim-3 and/or PD-1 expression on T cells are hallmarks of T cell exhaustion in chronic HIV and/or HCV infections [18], [19], [20]. In our cohort of osteosarcoma patients, TI T cells made up a significantly smaller fraction in mononuclear cells and contained significantly higher levels of TIM-3+ PD-1− cells and TIM-3+ PD-1+ cells, than their PB
Discussion
The main finding of this study is that CD163+ TAMs contributes to the exhaustion of tumor-infiltrating T cells and suppression of T cell proliferation and proinflammatory cytokine production. To demonstrate that, we first showed that PB T cells and TI T cells contained different frequencies of TIM-3+ PD-1− and TIM-3+ PD-1+ T cells, and that these frequencies in the same individual were not correlated, demonstrating that the elevated frequencies of TIM-3+ PD-1− and TIM-3+ PD-1+ T cells in tumor did
Conflict of interest
The authors declare no conflict interests.
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