Chordoma Foundation


PD-1/PD-L1 in Chordoma

Programmed Cell Death Protein 1 (PD-1) and its ligands PD-L1 and PD-L2 are part thought to play a role in suppressing the immune system. Tumor cells can exploit the PD-1 immune checkpoint pathway to evade immune cells that would normally attack them.
PD-1 proteins serve as receptors on the surface of T-cells (key players in immune response). When PD-L1 or PD-L2 binds to PD-1, it inactivates the T-cell and prevents it from attacking tumor cells. Ultimately, the interaction between PD-1 and its ligands serves to inhibit a host’s natural immune response to foreign antigens.

Expression of the PD-1/PD-L1 pathway has been implicated in the progression of a number of cancers, including both central nervous system tumors and solid tumors.1 2 Immune therapy strategies have been devised to break the interaction between the proteins, making cancer cells susceptible to attack by the cells of a host’s immune system. Immune therapy has received national attention as a possible breakthrough in cancer treatment.

Chordoma researchers have begun preliminary investigations of the PD-1/PD-L1 pathway in chordoma. Their findings are summarized below. Additional research is necessary to discern the role of immune inhibition in chordoma pathogenesis, and to explore whether a chordoma patient’s natural immune response could be harnessed to combat chordoma tumor cells.

Molecular Evidence

Gene Expression

  • Expression of PD-L1 and PD-L2 at the mRNA level has been confirmed in chordoma cell lines U-CH1 and U-CH2. Expression is shown to be up-regulated by exposure to IFN-gamma, an inflammatory cytokine associated with immune response.1
  • PD-L1 expression was significantly correlated with TNF-α and TNFR1 gene expression.3

Protein Expression

  • In one study 6 of 10  chordoma tumor samples analyzed showed infiltration of immune cells into chordoma tumors. In 3 of those 6, immune cells were found to express PD-1, and in 4 of 6 PD-L1 was expressed in membranous areas surrounding areas of tumor infiltration, though none of the samples showed robust expression.1 Another study found PD-1 and PD-L1 expressing tumor infiltrating lymphocytes in 22% and 11% of tumor samples tested, respectively.4
  • In another study, 74 of 78 chordoma samples were positive for PD-L1 expression. Twenty-three of the 78 had tumor-infiltrating lymphocytes (TILs), and those samples had significantly higher PD-L1 expression than those without TILs.5 In a more recent study, 37 of 37 samples were positive for expression of both PD-1 and PD-L1, and 12 had TILs. Again, samples that expressed PD-L1 were more likely to have TILs, and PD-L1 was significantly associated with advanced stages of chordoma.6 7
  • Chordoma cell lines U-CH1, U-CH2, and JHC7 showed variable, membranous expression of ligands PD-L1 and PD-L2 at basal levels. Exposure to IFN-gamma led to up-regulation of PD-L2 in all three lines but PD-L1 in only 2/3.1 A more recent study confirmed expression in U-CH1 and U-CH2 and demonstrated expression in cell line CH22. In this study, exposure to IFN-gamma led to up-regulation of PD-L1 in U-CH1 and U-CH2.5
  • PD-1 and PD-L1 were measured in tumor-infiltrating lymphocytes (TILs) in 54 chordoma cases. PD-1+ TILs density in the tumor interior was associated with surrounding muscle invasion by tumor whereas PD-L1+ TILs were inversely associated with tumor pathological grade and stage. The density of PD-1+ TILs and PD-L1+ TILs in the tumor interior and invasion margin were significantly associated with local recurrence-free survival and overall survival.8

Preclinical Evidence

In-vitro Efficacy

  • Avelumab: Co-culture of 4 chordoma cell lines with brachyury-specific CD8+ cells increased PD-L1 expression on chordoma cells through the production of IFN-γ. The increase in PD-L1 expression subsequently increased the cells’ sensitivity to NK-mediated cell lysis via the anti-PD-L1 monoclonal antibody avelumab. This suggests that avelumab is capable of inducing antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing chordoma cells.9

Clinical Evidence

Case Reports

  • Pembrolizumab: A patient with fast growing tumors that had failed to respond to standard therapies was treated with the PD-1 targeting antibody Pembrolizumab (200mg), which led to rapid clinical improvement, shrinkage of tumor bulk, and control of disease for 6 months. A subcutaneous metastasis in the patient showed strong up regulation of PD-L1, while PD-1 was negative before and after immunotherapy.10
  • Nivolumab: A patient who had undergone multiple surgeries and had been treated with imatinib and pazopanib was treated with the PD-1 targeting antibody Nivolumab (3mg/kg), which resulted in rapid major clinical improvement. The clinical response lasted 9 months before progression.10

Phase I Trial

  • M7824 (MSB0011359C): M7824 is a bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to a TGF-β “trap”. Treatment of a chordoma patient with 20mg/kg M7824 resulted in early progression and drug discontinuation on day 85 followed by late-onset tumor shrinkage observed on day 280 despite no further therapeutic interventions after discontinuing M7824.11

Open Clinical Trials

The following clinical trials have been launched to explore whether PD-1 inhibitors are effective in treating chordoma patients. Visit our Clinical Trials page to view a list of other clinical trials available to chordoma patients and to find out who to contact if you wish to participate.

Trial Identifier



NCT03173950 Phase II Trial of the Immune Checkpoint Inhibitor Nivolumab in Patients With Select Rare CNS Cancers National Cancer Institute (Bethesda, MD)
NCT02989636 Phase I Study of Stereotactic Radiosurgery With Concurrent and Adjuvant PD-1 Antibody Nivolumab in Subjects With Recurrent or Advanced Chordoma Johns Hopkins Hospital (Baltimore, MD) and Memorial Sloan Kettering Cancer Center (New York)
NCT03623854 A Signal Finding Phase 2 Study of Nivolumab (Anti-PD-1) and Relatlimab (Anti-LAG-3) in Patients With Advanced Chordoma UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California

Mathios D, Ruzevick J, Jackson C, et al. PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment. J Neurooncol. 2015;121(2):251-259. [PubMed]
Thanindratarn P, Dean D, Nelson S, Hornicek F, Duan Z. Advances in immune checkpoint inhibitors for bone sarcoma therapy. J Bone Oncol. 2019;15:100221.
Gulluoglu S, Tuysuz E, Sahin M, et al. The role of TNF-α in chordoma progression and inflammatory pathways. Cell Oncol (Dordr). June 2019.
Liang W, Millis S Z, Gatalica Z, Reddy SK, Little A, Van Tine B A. Identification of actionable targets in chordomas using a multiplatform molecular analysis, and response with targeted therapy [abstract]. ASCO Annual Meeting. Published 2015.
Feng Y, Shen J, Gao Y, et al. Expression of programmed cell death ligand 1 (PD-L1) and prevalence of tumor-infiltrating lymphocytes (TILs) in chordoma. Oncotarget. 2015;6(13):11139-11149. [PubMed]
Zou M, Peng A, Lv G, et al. Expression of programmed death-1 ligand (PD-L1) in tumor-infiltrating lymphocytes is associated with favorable spinal chordoma prognosis. Am J Transl Res. 2016;8(7):3274-3287. [PubMed]
Zou M, Guo K, Lv G, et al. Clinicopathologic implications of CD8<sup>+</sup>/Foxp3<sup>+</sup> ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients. Cancer Immunol Immunother. October 2017. [PubMed]
Zou M, Lv G, Wang X, et al. Clinical Impact of the Immune Microenvironment in Spinal Chordoma: Immunoscore as an Independent Favorable Prognostic Factor. Neurosurgery. July 2018. [PubMed]
Fujii R, Friedman E, Richards J, et al. Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab. Oncotarget. 2016;7(23):33498-33511. [PMC]
Migliorini D, Mach N, Aguiar D, et al. First report of clinical responses to immunotherapy in 3 relapsing cases of chordoma after failure of standard therapies. Oncoimmunology. 2017;6(8):e1338235. [PubMed]
Strauss J, Heery C, Schlom J, et al. Phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in advanced solid tumors. Clin Cancer Res. January 2018. [PubMed]

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