Tumor-Infiltrating T Cells and the PD-1 Checkpoint Pathway in Advanced Differentiated and Anaplastic Thyroid Cancer

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Abstract

Context:

Five to 10% of patients with differentiated thyroid cancers (DTC) develop invasive and/or distant metastatic disease that is marginally improved with standard therapies. Prognosis is poor for patients with anaplastic thyroid cancer, with a median survival of 3–5 months. We suggest that a paradigm shift is necessary in the treatment of advanced cases.

Objective:

We hypothesized that a T-cell response is generated in advanced thyroid cancer and may be a viable therapeutic target.

Design:

Primary DTCs were analyzed by quantitative RT-PCR (n = 92) for expression of CD3, CD8, forkhead box (Fox)-P3, programmed death (PD)-1, PD-1 ligand-1, and PD-1 ligand-2 and biopsied for cellular analysis by flow cytometry (n = 11). Advanced pT4 cases (n = 22) and metastases (n = 5) were analyzed by immunohistochemistry.

Setting:

The study was conducted at the University of Colorado Hospital.

Patients:

Thyroid cancer patients undergoing thyroidectomy or completion surgery for advanced disease between 2002 and 2013 participated in the study.

Intervention:

There were no interventions.

Main Outcome Measure:

Immune markers were analyzed for association with disease severity.

Results:

Immune markers were commonly expressed at the RNA level. PD-L1 was higher (P = .0443) in patients with nodal metastases. FoxP3+ (P < .0001), PD-1+CD8+ (P = .0058), and PD-1+CD4+ (P = .0104) T cells were enriched in DTC biopsies. CD8+ and FoxP3+ T cells were detected by immunohistochemistry in all pT4 tumors and a subset of metastases. PD-1+ lymphocytes were found in 50% of DTCs. PD-L1 was expressed by tumor and associated leukocytes in 13 of 22 cases, and expression was more diffuse in anaplastic thyroid cancer (P = .0373). BRAFV600E mutation was associated with higher frequencies of tumor-associated lymphocytes (P = .0095) but not PD-L1 expression.

Conclusions:

PD-1 checkpoint blockades may have therapeutic efficacy in patients with aggressive forms of thyroid cancer.

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