T cell-tumor interaction directs the development of immunotherapies in head and neck cancer

Abstract

The competent immune system controls disease effectively due to induction, function, and regulation of effector lymphocytes. Immunosurveillance is exerted mostly by cytotoxic T-lymphocytes (CTLs) while specific immune suppression is associated with tumor malignancy and progression. In squamous cell carcinoma of the head and neck, the presence, activity, but also suppression of tumor-specific CTL have been demonstrated. Functional CTL may exert a selection pressure on the tumor cells that consecutively escape by a combination of molecular and cellular evasion mechanisms. Certain of these mechanisms target antitumor effector cells directly or indirectly by affecting cells that regulate CTL function. This results in the dysfunction or apoptosis of lymphocytes and dysregulated lymphocyte homeostasis. Another important tumor-escape mechanism is to avoid recognition by dysregulation of antigen processing and presentation. Thus, both induction of functional CTL and susceptibility of the tumor and its microenvironment to become T cell targets should be considered in CTL-based immunotherapy.

Figure 1

Immune escape variants of cells in the tumor indicate an effective T cell response. HPV infection leads to unregulated cell proliferation and accumulation of chromosomal aberration. Cumulative genetic alterations in tumor cell subclones lead to the emergence of tumor cell variants with divergent characteristics, for example, loss of HLA expression. Selection pressure is exerted by the microenvironment of the tumor and immune response mechanisms. Over time, susceptible cells will be eliminated and resistant cells will regrow, to form a tumor consisting of predominantly immunoresistant cells and compromising immunotherapeutic strategies.

Figure 2

Comparison of the effects of a failed conventional therapy and the outcome of a hypothetical CSC-targeted immunotherapy. Currently applied conventional therapies target bulk tumor cells that are less resistant than CSC. This leads to initial shrinking of the tumor mass but eventually regrowth from residual CSC. An immunotherapeutic approach targeting CSC directly would cut off the rejuvenating supply of CSC and ultimately lead to tumor regression.