Cancer-related inflammation is considered the "seventh hallmark of cancer"; numerous studies demonstrate that tumors develop and progress within inflammatory diseases. Central to the development of cancer are genetic changes that endow these cancer cells with many of the hallmarks of cancer, such as self-sufficient growth and resistance to anti-growth and pro-death signals. However, while the genetic changes that occur within cancer cells themselves, such as activated oncogenes or dysfunctional tumor suppressors, are responsible for many aspects of cancer development, they are not sufficient. Tumor promotion and progression are dependent on ancillary processes involving cells of the tumor environment that are not necessarily cancerous themselves. Infiltration of immune cells facilitates tumor development through the production of factors that promote carcinogenesis and by enabling tumors to evade the host immune response. Small molecules including cytokines, chemokines, and growth factors play key roles in both inflammation and cancer by promoting proliferation, angiogenesis, and carcinogenesis and by recruiting immune cells. The extracellular matrix is altered in inflammation and provides structural support to developing tumors. Hypoxia is a common state in cancers and inflamed tissues which causes DNA damage and induces tumorigenic factors. Finally, tissue vasculature is a vital part of its microenvironment, supplying oxygen, nutrients, and growth factors to rapidly dividing cells and providing a mechanism for metastatic spread. This review will discuss the reflexive relationship between cancer and inflammation with particular focus on how by considering the role of inflammation in physiologic processes such as the maintenance of tissue homeostasis and repair may provide a logical framework for understanding the connection between the inflammatory response and cancer. The cells and molecules outlined here represent potential targets for the treatment of head and neck cancer.

While viral antigens in HPV-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from stage III–IV OPC patients undergoing concomitant chemoradiotherapy (CRT) with or without induction chemotherapy. Circulating immunocytes including CD4+ and CD8+ T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T cell assays in the presence of blocking antibody. While HPV-specific T cell responses were present in 13/18 patients prior to treatment, 10/13 patients lost these responses within 3 months after CRT. CRT decreased circulating T cells and markedly elevated MDSC. PD-1 expression on CD4+ T cells increased by nearly 2.5-fold after CRT, and ex-vivo culture with PD-1 blocking antibody enhanced HPV-specific T cell responses in 8/18 samples tested. CRT suppresses circulating immune responses in HPVOPC patients by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4+ T cells. These data strongly support testing of PD-1-blocking agents in combination with standard-of-care CRT for HPVOPC.

3b.

Clinical characteristics of high-risk non-HPV16 OPC were largely consistent with those of HPV16 OPC. Additional multi-institutional studies will be required to demonstrate conclusively that the favorable prognosis of patients with HPV16 applies to all high-risk HPV types. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1330-1337, 2016.