Immune Response Against Head and Neck Cancer: Biological Mechanisms and Implication on Therapy

Abstract

Head and neck carcinoma (HNC) are diseases arising from several tracts of the aerodigestive ways. Most HNC are squamous cell carcinoma (SCCHN). Immunotherapy is a treatment strategy aimed to reinforce the immune system. Several types of immunotherapy are available in the clinical scenario. Checkpoint inhibitors were developed later in SCCHN; nivolumab and pembrolizumab have reached the clinical approval, having both drugs demonstrated to significantly improve the overall survival, if compared with the standard of treatment (according to the results of the CheckMate 141 and KEYNOTE-040 trials). Nevertheless, immunotherapy may fail because of the genetics of SCCHN. In fact, two genetically different types of SCCHN have been discovered, one virus-related (HPV) and the other mutagens-related. They seem to show in clinical trials very different responses to immunotherapy. Given the existence of a number of factors predictive of response to immunotherapy in SCCHN, a future clinical approach may be to characterize the genetic and immunologic feature of SCCHN and to perform a well-tailored immunotherapy. This review will summarize the main immunotherapy strategies available in SCCHN, discussing their real efficacy, highlighting also the ways to improve them.

Figure 1

Immune response against cancer may be divided in three phases: 1) the innate immune response that happens in the tumor site, 2) the activation of specific T-cells against cancer, in the lymph nodes and 3) the killing of tumor cells operated by the CD8+ T-cells, which migrates in the tumor site.

Figure 2

Mechanisms through which Treg can dampen the cytotoxic immune response CD8+ mediated: Tregs interact with antigen presenting cells (APC) through CTLA-4, seizing them from the microenvironment; the linkage between PD-1 and PDL-1 expressed by tumor cells allows that lasts to survive; CD39 and CD73 convert ATP in ADP, which is known to be a strong suppressor of the APC activity; finally, Treg interact directly with tumor cells through the linkage between TIM-3 and Galectin-9, resulting in their further stimulation.

Figure 3

Therapeutic vaccines available. DNA, mRNA, cancer peptides, viral vector containing immunogenic constructs or irradiated cancer cells may be directly administered eliciting an immune response against cancer. In alternative, DC may be stimulated with cytokines and tumor associated antigens (TAA) and then injected in patients.

Figure 4

CTL-based nasopharyngeal adoptive therapy. Reinfusion of EBV-antigens restricted cytotoxic T-lymphocytes (EBV-CTLs), following ex vivo activation of autologous T-cells in presence of IL-2 and lymphoblastoid cell lines (LCLs), represented by EBV-infected immortalized B-lymphocytes. PBMC: peripheral blood mononuclear cells; EBV: Epstein–Barr virus; LCL: lymphoblastoid cell lines; DC: dendritic cells; CTL: cytotoxic T-lymphocytes; IL-2: interleukin-2.

Figure 5

First (1G), second (2G), and third (3G) generation CAR, depending on the presence in the molecule of none, one or more costimulatory domain. Courtesy of Perri F et al. WCRJ 2018; 5 (1): e1042.

Figure 6

The two main phases during which TME (tumor microenvironment) can inhibit T-Cells function and the possible therapies able to circumvent this phenomenon.