Original ArticlePrognostic Significance of Programmed Death Ligand 1 Expression and Tumor-Infiltrating Lymphocytes in Axial Osteosarcoma
Introduction
Osteosarcoma is the most common primary bone malignancy, affecting predominantly young individuals, with a worldwide incidence of approximately 3 cases per million persons per year, whereas a subclassification of the disease affecting the axial skeleton is relatively rare and primarily occurs in the elderly, representing 10%–20% of all osteosarcoma cases.1, 2, 3, 4, 5 A combination of curative resection and neoadjuvant chemotherapy and/or radiotherapy is the primary treatment approach for osteosarcoma, with an overall 5-year survival of 70%, although this rate is <40% for axial osteosarcoma.3, 4, 5 No substantial progress has been achieved over the past 3 decades for this condition. One challenge linked to the dismal prognosis of axial osteosarcoma is the surgical complexity of resecting tumors from the affected individual because of the axis-specific anatomic site proximal to vital organs. The treatment strategies for axial osteosarcoma remain controversial, with few comprehensive and robust datasets available. Increasing numbers of reports have cited the immune microenvironment as an important driver of the course of tumor development and progression in solid tumors.6, 7, 8, 9 Furthermore, recent research highlights the relevance of identifying immune-related biomarkers in situ to improve risk stratification and advance immune-based therapeutic treatment of patients with cancer.10, 11, 12 Likewise, programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis and tumor-infiltrating lymphocyte (TILs) also had clinically relevant and therapeutic value in osteosarcoma; however, little is known concerning the immune microenvironment in axial osteosarcoma.13, 14, 15 Thus, there is a critical need for continuous research work characterizing the immune microenvironment of patients with axial osteosarcoma with the goal of improving patient survival.
Assessing the prognostic relevance of the immune microenvironment has the advantage of reducing the impact of tumor heterogeneity on predicting outcomes, and there has been great interest in characterizing immune prognostic biomarkers, especially exemplified by the PD-1/PD-L1 axis and cluster of differentiation 8–positive (CD8+) TILs.16, 17, 18 TILs serve as a primary defensive cell type necessary for controlling cancer progression.19, 20, 21, 22 PD-L1 is expressed by most cells, particularly in immune-privileges sites where it binds to PD-1, and this marker is further adaptively expressed by tumor cells.23 There has been robust evidence that the interaction between PD-1 in lymphocytes and PD-L1 in tumor cells can incapacitate defensive TILs via inhibitory signaling, thereby sparing tumor cells from the host immune response.8, 20, 24, 25 In addition, the clinically relevant role of the PD-1/PD-L1 axis and of intratumoral infiltrates has therefore been proposed by multiple studies. For example, PD-L1 expression in situ is closely associated with clinicopathologic features and clinical outcomes in breast cancer, gastric cancer, and non-small-cell lung cancer.26, 27, 28 Consistent with this association, immunotherapy regimens targeting the PD-1/PD-L1 axis and T-cell adoptive immunotherapy have shown great potential as means of boosting spontaneous antitumor responses primarily mediated by CD8+ T lymphocytes, thus prolonging disease stabilization in patients with cancer, including osteosarcoma.29, 30, 31, 32 Furthermore, recent work has strongly suggested that tumor histologic responses to chemotherapy are related to the levels of PD-L1/PD-1 expression and/or of lymphocytic infiltration within the immune microenvironment.33, 34, 35
Given those findings, identifying immunologic parameters with prognostic significance has the potential to help better predict patient outcomes and design immunomodulatory therapeutic interventions for the treatment of axial osteosarcoma. In this study, we therefore sought to characterize the immune microenvironment by examining both the PD-1/PD-L1 axis and intratumoral TILs by immunohistochemistry (IHC) in a large cohort of patients with primary axial osteosarcoma. We then used the resultant data to evaluate the clinicopathologic and prognostic value of measured immune parameters.
Section snippets
Patient Cohort and Tissue Specimens
Our institutional ethics review board approved all sample collection and data retrieval for this study. Informed consent was obtained from each patient before conducting this research. In this study cohort, 69 patients diagnosed between March 2005 and June 2013 with pathologically confirmed osteosarcoma primarily arising at the axial skeleton were included (representative magnetic resonance images [MRIs] are shown in Figure 1). Patients with any other comorbidities (e.g., autoimmune diseases on
Patient Characteristics
A total of 69 patients with axial osteosarcoma were included (representative MRIs are shown in Figure 1). Of these patients, 34 had tumors primarily occurring in the head, 23 in the spine, 5 in the pelvis, and 7 in the ribs (Table 1). The mean age of patients in this cohort was 37.5 years (range, 8–81 years) (Table 1). All patients underwent surgical operations and 33 patients also received a neoadjuvant chemotherapy regime at our institute under the same guidelines. All patients were subjected
Discussion
The mean age of patients in this cohort was 37.5 years, and the ratio of males to females was 1.6:1. These demographics were consistent with the propensity of axial osteosarcoma to affect the elderly as reported in the SEER (Surveillance Epidemiology and End Results) program database.5, 39, 40, 41 In our study cohort, the median EFS and median OS were 7.0 and 19.0 months, respectively. The EFS and OS at 2 years were 15.9% and 42.4%, respectively. Furthermore, the 5-year OS decreased to just
Conclusions
Our results suggest that the immune microenvironment is of clinically relevant significance in patients with primary axial osteosarcoma. Specifically, we identified CD8+ TILs and PD-L1+ TILs both as independent favorable prognostic markers. Further investigations into the immune microenvironment of axial osteosarcoma are warranted to further validate our conclusions.
Acknowledgments
The authors thank Professor Chen for the English review and editing of the manuscript. The authors also thank Professor Fan (pathologist) for his effort in assessing tumor samples and Dr. Zou for his technical assistance.
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2022, Cancer LettersCitation Excerpt :Meanwhile, PD-1 expression level was generally lower than PD-L1 [24,25,30,35,39,41,44,46]. Many studies have shown that higher PD-L1 expression is correlated with poor prognosis in osteosarcoma patients, while a similar association was also observed with PD-1 expression [24,25,31,33–37,41,42]. Despite discrepancies in a few studies, the relationship between PD-L1 expression and osteosarcoma recurrence or metastasis has been demonstrated [25,26,29–31,33,34,37,43–45,47].
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.