![]() ![]() Moreover, the cytotoxic properties of NK cells are inhibited via TGF- β1 overexpression that leads to reduced expression of NK cell receptors KHG2D and CD16 ( 14). ![]() For example, in HNSCC, the tumor-infiltrating T cells can be compromised via functional defects leading to decreased proliferation in response to cytokines, impaired ability to kill tumor cells, and suppressed IL-1 and/or IFN-γ production ( 9– 13). HNSCC, like other cancers, can evade or suppress the immune response at each of these steps. Then finally T cells bind to the target cancer cells via their T cell receptors (TCR) and kill them via multiple mechanisms ( 7, 8). Next, effector T cells are activated and then migrate to and infiltrate the tumor microenvironment ( 5, 6). The process begins with the release of cancer neoantigens and their uptake by antigen-presenting cells such as dendritic cells (DC) with subsequent required signaling to move forward with presentation on MHC I and MHC II molecules to T cells ( 4). Numerous steps need to occur in order for the immune system to achieve effective cancer killing. The cancer immunoediting theory hypothesizes that at first the immune system recognizes and eliminates all cancer cells, then the cancer evades the immune system such that only equilibrium is achieved in which tumor growth is controlled but not eradicated, followed by the “escape” phase whereby the tumor fully eludes the immune system and progresses clinically ( 3). The Tumor Immune Microenvironment in HNSCCĪntitumor immunity is a back-and-forth duel between the immune system and the cancer. In this review we detail the current status of immunotherapy in R/M HNSCC, predictive biomarkers, and future directions in the field. Immunotherapy has changed our standard-of-care approach and improved outcomes in this setting, but there is still more work to do to continue to move the needle forward. In the recurrent/metastatic (R/M) setting there is a great need for improvement in outcomes, especially when treatment is with systemic therapy alone. While the majority of squamous cell carcinoma of the head and neck (HNSCC) patients present at a stage where therapy is definitive, with only 10% presenting with distant metastatic disease, a large proportion of patients, especially HPV negative HNSCC, will recur. In addition to traditional risk factors of smoking and alcohol, there are two virally driven cancers, the Epstein Barr Virus (EBV) in the nasopharynx and the Human Papillomavirus (HPV) in the oropharynx, with the latter associated with a significantly better prognosis ( 2). Head and neck cancer is the 6 th most common cancer worldwide, and while it includes many histologies, squamous cell carcinoma represents 90% of diagnosis, with the most common primary sites being oral cavity, hypopharynx, larynx, and oropharynx ( 1).
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