Harnessing shared antigens and T-cell receptors in cancer: Opportunities and challenges

Blockade of inhibitory immune checkpoints (ICPs) has led to impressive clinical regressions in some patients with tumors like lung cancer or melanoma, which often carry a high mutational load (1). Somatic mutations expressed by tumor cells can provide a rich source of neoantigens, and it has been suggested that T cells against these antigens may be targets of ICP blockade (2, 3). Because the targets of somatic mutations typically differ in individual tumors, neoantigen-specific T cells exhibit little shared reactivity. However, mutational loads in human cancers vary greatly, and several solid tumors (e.g., hormone receptor-positive breast cancer, ovarian cancer, colon cancer), as well as hematological or pediatric tumors, often carry a much lower mutational burden (4). Interestingly, even in tumor types that typically do not express high mutational burden, the degree of T-cell infiltration predicts improved survival (5). There is an unmet need to understand and harness the properties of T cells infiltrating such tumors better. In PNAS, Munson et al. (6) identify several shared T-cell receptors in T cells infiltrating HLA A2+ human breast cancers. These findings may set the stage for novel approaches to harness these T cells for therapy or prevention. Most of the tumor-infiltrating T lymphocytes (TILs) express αβ T-cell receptor (TCR), with … [↵][1]1To whom correspondence may be addressed. Email: kavita.dhodapkar{at}yale.edu or madhav.dhodapkar{at}yale.edu. [1]: #xref-corresp-1-1