Fear, Vanessa S., Forbes, Catherine A., Neeve, Samuel A., Fisher, Scott A., Chee, Jonathan, Waithman, Jason, Ma, Shao Kang, Lake, Richard, Nowak, Anna K., Creaney, Jenette, Brown, Matthew D., Saunders, Christobel, and Robinson, Bruce W. S.
Subjects
T cells, LUNGS, IMMUNOTHERAPY, METASTASIS, TUMORS
Abstract
A correction to this paper has been published: https://doi.org/10.1007/s00262-021-02970-z [ABSTRACT FROM AUTHOR]
T cells, THERAPEUTICS, IMMUNE checkpoint inhibitors, TUMOR-infiltrating immune cells, T cell receptors, TUMORS
Abstract
Immune checkpoint inhibitors against PD-1, PD-L1 and CTLA-4 have altered the treatment paradigm for various types of cancers in the past decade. However, they offer clinical benefits to only a subset of patients. Evaluation and identification of an appropriate therapeutic approach to improve intratumoral immune status are needed for better treatment outcomes. We previously demonstrated that intratumoral expression of IL-7 and IL-12 increased tumor-infiltrating lymphocytes in poorly immunogenic tumors, resulting in a higher tumor regression rate than IL-12 alone. However, the mechanism underlying the difference in efficacy with and without IL-7 remains unclear. Here, we identified a previously unknown effect of IL-7 on the T cell receptor (TCR) repertoire of intratumoral CD8+ T cells, which is induced in the presence of IL-12. While IL-7 alone increased the diversity of intratumoral CD8+ T cells, IL-7 with IL-12 increased a limited number of high-frequency clones, conversely augmenting IL-12 function to increase the clonality. The proportion of mice with multiple high-frequency clones in tumors correlated with that achieving complete tumor regression in efficacy studies. These findings provide a scientific rationale for combining IL-7 and IL-12 in anticancer immunotherapy and unveil a novel IL-7 function on intratumoral TCR repertoire. [ABSTRACT FROM AUTHOR]