Hitting the Target: How T Cells Detect and Eliminate Tumors

Abstract

The successes of antitumor immuno-based therapies and the application of next-generation sequencing to mutation profiling have produced insights into the specific targets of antitumor T cells. Mutated proteins have tremendous potential as targets for interventions using autologous T cells or engineered cell therapies and may serve as important correlates of efficacy for immunoregulatory interventions including immune checkpoint blockade. As mutated self, tumors present an exceptional case for host immunity, which has primarily evolved in response to foreign pathogens. Tumor Ags' resemblance to self may limit immune recognition, but key features appear to be the same between antipathogen and antitumor responses. Determining which targets will make efficacious Ags and which responses might be elicited therapeutically are key questions for the field. Here we discuss current knowledge on antitumor specificity, the mutations that provide immunogenic targets, and how cross-reactivity and immunodominance may contribute to variation in immune responses among tumor types.

Figure 1. Features that determine anti-tumor T cell reactivity

Two major types of antigens, tumor-associated and tumor-specific, can be recognized by endogenous T cell responses. The ability for epitopes derived from these antigens to be detected by responding T cells is modulated by the host’s HLA type and the epitope’s processing and presentation efficiency. Intratumoral heterogeneity may also allow individual tumor cells to escape recognition. On the T cell side, immunodominance hierarchies can be generated leading to an individual antigen being the major target of the response. Additionally, holes in the TCR repertoire and T cell tolerization and exhaustion can limit response efficacy.