The Potential of Donor T-Cell Repertoires in Neoantigen-Targeted Cancer Immunotherapy

Abstract

T cells can recognize peptides encoded by mutated genes, but analysis of tumor-infiltrating lymphocytes suggests that very few neoantigens spontaneously elicit T-cell responses. This may be an important reason why immune checkpoint inhibitors are mainly effective in tumors with a high mutational burden. Reasons for clinically insufficient responses to neoantigens might be inefficient priming, inhibition, or deletion of the cognate T cells. Responses can be dramatically improved by cancer immunotherapy such as checkpoint inhibition, but often with temporary effects. By contrast, T cells from human leukocyte antigen (HLA)-matched donors can cure diseases such as chronic myeloid leukemia. The therapeutic effect is mediated by donor T cells recognizing polymorphic peptides for which the donor and patient are disparate, presented on self-HLA. Donor T-cell repertoires are unbiased by the immunosuppressive environment of the tumor. A recent study demonstrated that T cells from healthy individuals are able to respond to neoantigens that are ignored by tumor-infiltrating T cells of melanoma patients. In this review, we discuss possible reasons why neoantigens escape host T cells and how these limitations may be overcome by utilization of donor-derived T-cell repertoires to facilitate rational design of neoantigen-targeted immunotherapy.

Keywords: T cell; allogeneic hematopoietic stem cell transplantation; donor; donor lymphocyte infusion; graft versus tumor effect; immunotherapy; minor histocompatibility antigen; neoantigen.

Figure 1

Identification of immunogenic neoantigens is the major technical challenge in genome-based personalized immunotherapy. 1. Advances in sequencing techniques and computational sequence analysis tools have enabled rapid identification of somatic mutations in expressed genes that are capable of generating potential neoantigens. Human leukocyte antigen (HLA) binding affinity algorithms can narrow down the number of potential neoantigens, but are insufficient in predicting aspects contributing to immunogenicity. 2. Nontolerized T-cell repertoires of healthy donors HLA-matched with the patient can be used to identify neoepitopes (A), and T-cell receptors (TCRs) from the neoantigen-responsive donor T cells can be isolated (B). 3. The identified neoantigens can be used for therapeutic vaccination to (prime and) expand neoantigen-specific T cells in the patient repertoire (A). Alternatively, the TCRs identified from the neoantigen-responsive donor T cells can be used to retarget patient T cells to recognize the tumor (B). WES, whole-exome sequencing; RNAseq, RNA sequencing.