Salivary gland cancer in the era of immunotherapy: can we exploit tumor microenvironment?

ABSTRACT

Introduction

Salivary gland cancers (SGCs) consist of a rare family of neoplasms with varying histology and biological behavior. Therapeutic regimens have been relatively unchanged for decades. The recent successes of immunotherapy have raised hopes for the development of more effective strategies in SGC, thus emphasizing the role of tumor microenvironment (TME) in the design for more effective therapies.

Areas covered

This review presents an overview of the current knowledge on the pathobiology of SGC TME and discusses the potential of immunotherapeutic targeting.

Expert opinion

Most data on the role of TME in SGC carcinogenesis are derived from preclinical studies. Signaling cascades of immunotherapeutic interest, PD-1/PD-L1 and PD-1/PD-L2, are active in many SGCs and might be associated with biological behavior and prognosis. Immunotherapeutic attempts are very limited, but recent findings in other tumors on the role of exosomes and PD-L2 signaling suggest that TME of SGCs warrants further research, emphasizing larger cohorts, histology-based stratification, and standardized evaluation of immunomodulatory molecules, to explore the potential of targeting tumor stroma and its signaling cascades. Furthermore, combination of immunotherapies or immunotherapies with the antineoplastic agents targeting AR, HER2, and tyrosine kinases, recently introduced in SGC treatment, constitutes a promising approach for the future.

KEYWORDS:

• Salivary gland cancer
• tumor microenvironment
• PD-1/PD-L1
• PD-L2
• cancer-associated fibroblasts
• tumor-associated macrophages
• cancer stem cells

Article highlights

• Salivary gland cancer (SGC) microenvironment components co-orchestrate carcinogenesis with tumor cells, but their underlying pathways are subject to further research.

• Cancer-associated fibroblasts and tumor-associated macrophages promote SGC neovascularization and metastasis.

• PPD-L1 expression i/PD-L1 expression in SGC varies among different histological types and it is inconsistent among different studies.

• PD-L2 might indicate an alternative immune evasion pathway and thus should be evaluated further.

• Better study design, emphasis on exosomes and PD-L2 signaling, and focus on immunotherapies combination are required in SGC research

This box summarizes key points contained in the article.

Acknowledgments

The work of the authors was co-funded by the European Union (ESF) and Greek national funds through the Operational Program “Human Resources Development, Education and Lifelong Learning,” project title “Immunohistochemical Investigation of Angiogenesis and Biological Behavior of Salivary Gland Tumours” (project code: 5007067).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• Salivary gland cancer (SGC) microenvironment components co-orchestrate carcinogenesis with tumor cells, but their underlying pathways are subject to further research.

• Cancer-associated fibroblasts and tumor-associated macrophages promote SGC neovascularization and metastasis.

• PD-1/PD-L1 expression in SGC varies among different histological types and it is inconsistent among different studies.

• PD-L2 might indicate an alternative immune evasion pathway and thus should be evaluated further.

• Better study design, emphasis on exosomes and PD-L2 signaling, and focus on immunotherapies combination are required in SGC research

This box summarizes key points contained in the article

Additional information

Funding

This paper was not funded.