Precision and Immunoprevention Strategies for Tobacco-Related Head and Neck Cancer Chemoprevention

Abstract

To date, there is no FDA-approved chemoprevention approach for tobacco-related HNSCC. Effective chemoprevention approaches validated in sufficiently powered randomized trials are needed to reduce the incidence and improve survival. In this review, we recap the challenges encountered in past chemoprevention trials and discuss emerging approaches, with major focus on green chemoprevention, precision prevention, and immunoprevention. As our current depth of knowledge expands in the arena of cancer immunotherapy, the field of immunoprevention is primed for new discoveries and successes in cancer prevention.

Keywords: Chemoprevention; Head and neck squamous cell carcinoma (HNSCC); Immunoprevention; Smoking.

Fig. 1

Model of tobacco-related turmorigenesis and immunoediting. The figure is a simplified model of the evolution of immunoediting as it occurs throughout the process of tobacco-related HNSCC malignant transformation. Elimination in this stage “normal” tobacco-exposed mucosa is capable of identifying and eliminating tumor cells. The microenvironment typically is dominated by Th1, Th2, and Th17 T cells. M1-inflammatory macrophages, NK cells (both functional and dysfunctional), and dendritic cells (with tradition or altered phenotypes) can also be observed. Primary strategies for immunoprevention at this stage may serve to reduce chronic inflammation, or detoxify tobacco-related carcinogens. Equilibrium in this stage the emergence of immunosuppressive features imposes selective pressures on abnormal premalignant cells. Some premalignant lesions may spontaneously regress while others transform into malignancies. These lesions are characterized by the infiltration of Th1-dominated T cells, proinflammatory mediators, and presence of regulatory T cells (Treg), M2-immunosuppressive macrophages (M2), and myeloid-derived suppressors cells (MDSC). PD-L1 expression is also apparent at this stage. Key chemoprevention targets at this stage include blockade of chronic inflammation via COX2 inhibition, and PD-1/PD-L1 checkpoint inhibition. Escape-HNSCC tumors are consider to be largely immunosuppressive in nature. HNSCC tumors are characterized by the presence of multiple immunoevasive features including expansion of immunosuppressive M2 macrophages, MDSCs, Tregs, and tolerogenic dendritic cells (TDC), upregulation of checkpoint molecules PD-1/PDL1 and TIM-3, and immune evasive mechanisms such as expression of soluble and membrane-bound Fas ligand (FasL)