Mechanisms of resistance to T cell-based immunotherapy in head and neck cancer

Background: Most current approved or investigational immunotherapeutic approaches for head and neck squamous cell carcinoma are aimed at activating T cells. The majority of patients receiving such immunotherapy do not demonstrate durable tumor remission. Methods: Original articles covering tumor heterogeneity, immunoediting, immune escape, and local tumor immunosuppression were reviewed. Results: In the face of immune pressure, subclones susceptible to T cell killing are eliminated, leaving behind resistant tumor clones in a process known as immunoediting. Such subclones of tumor cells that are resistant to T cell killing may remain sensitive to natural killer (NK) cell detection and elimination, suggesting that patients harboring such tumors may benefit from combination of T and NK cell-based immunotherapy. Even in the setting of optimal immunotherapy, the immunosuppressive tumor microenvironment may arrogate effector immune responses through a number of distinct mechanisms. Conclusions: Highly effective immunotherapy will likely require multimodality approaches targeting independent mechanisms of immune activation.