PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPα axis in HPV negative head and neck squamous cell carcinoma

Abstract

Myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) play key roles in the tumor immune suppressive network and tumor progression. However, precise roles of programmed death-1 (PD-1) in immunological functions of MDSCs and TAMs in head and neck squamous cell carcinoma (HNSCC) have not been clearly elucidated. In the present study, we show that PD-1 and PD-L1 levels were significantly higher in human HNSCC specimen than in normal oral mucosa. MDSCs and TAMs were characterized in mice and human HNSCC specimen, correlated well with PD-1 and PD-L1 expression. αPD-1 treatment was well tolerated and significantly reduced tumor growth in the HNSCC mouse model along with significant reduction in MDSCs and TAMs in immune organs and tumors. Molecular analysis suggests a reduction in the CD47/SIRPα pathway by PD-1 blockade, which regulates MDSCs, TAMs, dendritic cell as well as effector T cells. Hence, these data identify that PD-1/PD-L1 axis is significantly increased in human and mouse HNSCC. Adoptive αPD-1 immunotherapy may provide a novel therapeutic approach to modulate the micro- and macro- environment in HNSCC.

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

“…More difficult to explain is the underlying cause for the more rapid decay in this immune activity in mice receiving PD‐1 antibody treatment compared to the mice receiving control treatment. It is important to note that, in the HNSCC environment, there are multiple mechanisms contributing to the immune dysfunction including inhibitory mediators such and PGE 2 produced directly by the tumor cells as well as tumor‐induced immune inhibitory cells such as Treg, MDSC and the less mature CD34 + progenitor cells, infiltrating macrophages and endothelial cells 10, 11, 12, 13, 14. Studies have not, however, been conducted to determine at what point and in what sequence during progression of premalignant oral lesions to HNSCC these various inhibitory mediators and cells overcome the immune defenses.…”

“…These include tumor production of immune inhibitory mediators and tumor induction of host immune suppressor cells. Among the immune suppressive cells induced by HNSCC are Treg, inhibitory tumor‐associated macrophages and fibroblasts, myeloid‐derived suppressor cells (MDSC) and the less mature CD34 + progenitor cells 10, 11, 12, 13, 14. More recently, attention has focused on mechanisms involving activation of immune checkpoint signaling such as through PD‐1 ligand and its PD‐1 receptor.…”

“…HNSCC cells and tumor‐infiltrating lymphocytes have been shown to express PD‐L1 and PD‐1, respectively 12, 19. In addition to expression of PD‐L1 on HNSCC tumor, tumor‐associated macrophages also express increased levels of PD‐L1, which would enable engagement of PD‐1 on intratumoral T‐cells 20.…”

“…In HNSCC patients, intratumoral Treg express higher levels of immune checkpoint receptors, including PD‐1 and this expression has been associated with their more pronounced immune inhibitory activity compared to that of circulating Treg 21. This increased expression of the PD‐1/PD‐L1 inhibitory pathway was seen in both HPV‐positive and HPV‐negative HNSCC 12, 19, 20. That the PD‐1/PD‐L1 axis mediates suppression was demonstrated in vitro by the increase in T‐cell proliferative response to activation on antibody blockade of PD‐1 19.…”

PD-1/PD-L1 biology and immunotherapy in HPV-positive oral cancers

“…A constant exposure with tumor antigen increases the activity of PD-1 on the surface of T cells which eventually generates a population of exhausted and abnormal T cells with aberrant signals to fight cancer cells. More recently, Sun and colleagues demonstrated that PD-1 overexpression is a general phenomenon irrespective of HPV status in head and neck cancers including oral cancer [13].…”