Increased recurrence and metastasis in patients whose primary head and neck squamous cell carcinomas secreted granulocyte-macrophage colony-stimulating factor and contained CD34+ natural suppressor cells

Abstract

Human head and neck squamous cell carcinomas (HNSCC) that produce high levels of granulocyte-macrophage colonystimulating factor (GM-CSF) have been shown to contain CD34 1 natural suppressor cells that inhibit the activity of intratumoral T-cells. The present study evaluated whether GM-CSF production and the presence of CD34 1 cells within primary HNSCC would translate into increased recurrence, metastasis or cancer-related death during the 2 years following surgical excision. Freshly excised primary HNSCC of 20 patients that subsequently developed disease, and of 17 patients that remained with no evidence of disease were analyzed for production of GM-CSF and for CD34 1 cell content. The cancers of patients that subsequently developed recurrences or metastatic disease produced almost 4-fold the levels of GM-CSF and had approximately 2.5-fold the number of CD34 1 cells as did cancers of patients that remained disease-free. In a second method of analysis, the prognostic significance of high vs. low GM-CSF and CD34 1 cell values was evaluated. These analyses showed that patients whose cancers produced high GM-CSF levels or had a high CD34 1 cell content had a disproportionately high incidence of recurrence or metastatic disease (94% and 100%, respectively), while the majority of patients whose primary cancers produced low levels of GM-CSF or had a low CD34 1 cell content remained disease-free (16% and 19%, respectively). Our results indicate that the presence of CD34 1 cells in GM-CSFproducing HNSCC is associated with a poorer prognosis for the cancer patients and suggest the utility of these parameters as prognostic indicators of outcome. Mechanistically, our results suggest that the presence of immune suppressive CD34 1 cells in GM-CSF-producing HNSCC leads to increased tumor recurrence or metastasis. Int. J. Cancer 74:69-74.r 1997 Wiley-Liss, Inc.Head and neck cancers, most of which are squamous cell carcinomas (HNSCC), are vulnerable to immune effector cells such as macrophages, natural killer cells and cytotoxic T-lymphocytes (Chikamatsu et al., 1995;Rabinowich et al., 1992). However, patients with HNSCC cancers are particularly prone to have defects in their immune defenses (Gooding et al., 1995;Hadden et al., 1994). Part of this immune suppression has been shown to be directly induced by soluble immune suppressive factors produced by the cancer (O'Mahony et al., 1993). However, cancers can also mediate immune suppression indirectly by stimulating immune suppressor cell activity. The immune suppressor cells that may be induced by human HNSCC have not been extensively studied or described, but have been well documented in many other cancer types of both humans and animals. Some human cancers induce suppressive T-cells that are inhibitory to immune functions, including anti-tumor T-cell reactivities (Chakraborty et al., 1991). Suppression of T-cell function in patients with HNSCC as well as with other cancers can also be due to monocytes or macrophages secreting the immune suppressive mediator prostaglandin E 2...

Computational Algorithm-Driven Evaluation of Monocytic Myeloid-Derived Suppressor Cell Frequency for Prediction of Clinical Outcomes

“…Clinically significant m-MDSC accumulation characterized with diverse myeloid phenotypic markers has been observed in a number of malignancies in humans (4–10). Young et al measured CD34 + natural suppressor cells and found that excess of CD34 + cells at the tumor site was associated with relapse of head and neck cancer.…”

Tadalafil Reduces Myeloid-Derived Suppressor Cells and Regulatory T Cells and Promotes Tumor Immunity in Patients with Head and Neck Squamous Cell Carcinoma

“…3) recruitment at the tumor site is a negative prognostic factor and is associated with an increased rate of metastasis and recurrence in HNSCC (4). Furthermore, the increased frequency of CD34 + MDSC in the peripheral blood mononuclear cells (PBMC) of patients with HNSCC has also been correlated with suppression of amnestic responses to recall antigens (5).…”

Effect of the Premalignant and Tumor Microenvironment on Immune Cell Cytokine Production in Head and Neck Cancer

“…Because of the aggressive nature of the disease, the five-year survival rate remains around 50%, despite some advances in treatment over that last 30 years. HNSCC patients are characterized by systemic immunosuppression, exhibiting increased populations of regulatory T cells and CD34 + progenitor cells, which suppress CD8 + T cell- and CD4 + helper T cell-mediated immunity at the primary tumor site and are associated with a poorer prognosis [3,4,5,6]. It is well defined that established HNSCC is associated with increased levels of suppressive immune cells [6,7], but how the tumor directly modulates the immune response is less clear.…”

“…[22]. Tumor-secreted GM-CSF has been shown to promote MDSC recruitment and differentiation, and high levels of GM-CSF in HNSCC patients are associated with a poorer prognosis [5,23]. Increased levels of PGE 2 are associated with invasion and angiogenesis in aggressive early-stage tumors [24].…”