© Springer International Publishing Switzerland 2017
Wojciech Golusiński, C. René Leemans and Andreas Dietz (eds.)HPV Infection in Head and Neck CancerRecent Results in Cancer Research20610.1007/978-3-319-43580-0_19Cancer Immunology and HPV
(1)
Department of Otorhinolaryngology, University of Schleswig-Holstein Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
Abstract
HNSCC is a heterogeneous group of tumors located in the oral cavity, oropharynx, hypopharynx and larynx. Originally, tobacco and alcohol exposures were the main risk factors for HNSCC. In the last two decades, HPV infections have been identified as a risk factor for HNSCC, especially for oropharyngeal tumors. Whereas the HPV-induced oropharyngeal carcinomas predominantly express the HPV16 related E6 and E7 oncoproteins, the HPV-negative HNSCC are associated with an overexpression of p53. However, if the therapy successes for HPV-negative and HPV-positive HNSCCs are compared, there are significantly higher total survival rates for HPV-positive oropharyngeal tumors compared to HPV-negative tumors. It is important to understand this phenomenon in order to improve and adapt therapy concepts.
Keywords
ImmunologyImmune cell infiltrationMicroenvironmentImmunotherapy1 Cancer Immunology and HPV
HNSCC is a heterogeneous group of tumors located in the oral cavity, oropharynx, hypopharynx and larynx. Originally, tobacco and alcohol exposures were the main risk factors for HNSCC. In the last two decades, HPV infections have been identified as a risk factor for HNSCC, especially for oropharyngeal tumors, with the tonsil area being the most commonly affected area with 45–70 % HPV-positive cases (Mellin et al. 2002; Ritta et al. 2013).
More than 180 papilloma viruses have been identified to date, with approximately 120 genotypes isolated from humans. Whereas the HPV-induced oropharyngeal carcinomas predominantly express the HPV16 related E6 and E7 oncoproteins, the HPV-negative HNSCC are associated with an overexpression of p53 (Bernard et al. 2010).
However, if the therapy successes for HPV-negative and HPV-positive HNSCCs are compared, there are significantly higher total survival rates for HPV-positive oropharyngeal tumors compared to HPV-negative tumors (Gillison 2008; Ragin and Taioli 2007). It is important to understand this phenomenon in order to improve and adapt therapy concepts.
2 Immune Cell Infiltrations
Human solid tumor tissues are known to be infiltrated by various kinds of immune cells which are modulated within the tumor microenvironment (Hartmann et al. 2003; Heimdal et al. 2000; Pries and Wollenberg 2006; Veltri et al. 1986).
Several HPV-related immunologic features have been described in HNSCC.
In general, HPV-positive tumors have been shown to possess characteristic immune cell infiltrates compared to HPV-negative HNSCC. Recently, Partlova et al. 2015 have shown that HPV-positive tumors were infiltrated by significantly higher numbers of IFNgC CD8C T lymphocytes, IL-17C CD8C T lymphocytes, myeloid dendritic cells and proinflammatory chemokines. Furthermore, HPV-positive tumors had significantly lower expression of COX2 mRNA and higher expression of PD1 mRNA (Partlova et al.).
Spanos et al. 2009 have shown, for human and murine HPV-transformed cell lines, that neither radiation nor cisplatin therapy cured immune-incompetent mice, whereas in vivo, HPV-positive tumors were more sensitive to radiation and cisplatin treatment. Surprisingly, adoptive transfer of wild-type immune cells into immune-incompetent mice restored HPV-positive tumor clearance with cisplatin therapy. These data suggest that HPV-positive tumors are not more curable because of an increased epithelial sensitivity to cisplatin or radiation therapy, but because of an HPV-related immunity (Spanos et al. 2009).
These implications of a HPV-related immunity were corroborated by a study with an unselected group of 50 patients with HNSCC, where T lymphocytes were isolated from tumors and lymph nodes. Comprehensive investigations of the HPV16-specific T cell responses revealed a broad repertoire of CD41 T helper type 1 and type 2 cells, CD41 regulatory T cells and CD81 T cells reactive to HPV16. Heusinkveld et al. identified circulating HPV16-specific T cells in 63.6 % of the HPV-positive HNSCC, but only in 24.1 % of the HPV-negative HNSCC (Heusinkveld et al. 2012).
Similarly, Albers et al. found increased levels of T cells toward HPV16 E7 in HPV-positive HNSCC patients (Albers et al. 2005).
The local presence of HPV16-specific T cell immunity in HPV16-induced HNSCC was underlined by an additional study, which demonstrated increased infiltrations of CD3+ and FoxP3+ T cells in correlation with higher HPV16 copy numbers in solid HNSCC (Ritta et al. 2013).
Correspondingly, it has been shown that targeting CD137, which is an inducible receptor on activated T lymphocytes, synergizes with cisplatin and radiation therapy in HPV-positive HNSCC (Lucido et al. 2014).
Furthermore, increased amounts of effector memory and effector T cells were found in patients with human HPV-positive oropharyngeal squamous cell carcinomas, suggesting a virus-induced T cell activation (Turksma et al. 2013).
In addition, increased numbers of different types of antigen presenting cells such as myeloid dendritic cells (mDC), plasmacytoid dendritic cells (pDC), macrophages and monocytes have been found in HPV-associated HNSCC (Levovitz et al.). Comprehensive immune profiling using qRT-PCR and immunohistochemistry identified a significantly increased infiltration of HPV-positive HNSCC by CD20+ B cells, as well as by invasive margin FoxP3+ Treg (Russell et al. 2013).
Similar findings have recently been demonstrated for HPV-related cervical cancers, where the HPV infection was associated with macrophage differentiation, a compromised cellular immune response, an abnormal imbalance between type 1 T–helper cells (Th1) and Th2 cells, regulatory T cell infiltration, and downregulated DC activation and maturation (Song et al. 2015).
3 Microenvironment Modulation
All these different types of immune cells are known to release numerous cytokines and inflammatory mediators with proangiogenic and prometastatic effects, and the potential to drive tumor progression.
For example, IL-1 is produced by monocytes, macrophages, dendritic cells and various other cells, and in HNSCC IL-1α and IL-1β have also been demonstrated to modestly induce the production of gelatines, which are family members of the matrix metalloproteinases (MMPs) and contribute to tumor invasion and metastasis (Mann et al. 1995 ).
IL-1α was furthermore identified to promote the transcriptional activator NF-κB which is known to participate in various aspects of cancer induction and maintenance (Wolf et al. 2001).
TGFβ is known to inhibit the proliferation and function of T and B lymphocytes as well as the function of macrophages (Chen et al. 1999; Mann et al. 1992).
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