IL-7 coupled with IL-12 increases intratumoral T cell clonality, leading to complete regression of non-immunogenic 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.

Interleukin-7 Biology and Its Effects on Immune Cells: Mediator of Generation, Differentiation, Survival, and Homeostasis

“…Mamoru et al. demonstrated that when IL-7 was induced in the presence of IL-12, the diversity of intratumoral CD8+ T cells increased, and IL-12 function was augmented to promote clonality ( 22 ). Similarly, immunocomplexes of IL-7 and αIL-7 mAb M25 (IL-7/M25) were described as super-agonists, remarkably augmenting the size of the T-cell pool.…”

A novel cocktail therapy based on quintuplet combination of oncolytic herpes simplex virus-2 vectors armed with interleukin-12, interleukin-15, GM-CSF, PD1v, and IL-7 × CCL19 results in enhanced antitumor efficacy

“…Mamoru et al reported that IL-7 and IL-12 expression of recombinant vaccinia viruses increased tumor-infiltrating lymphocytes in the LLC lung cancer model, leading to a better tumor therapy efficacy than IL-12 alone. And they demonstrated that IL-7 and IL-12 combination virotherapy could increase the intratumoral CD8 + T cells clonality and anti-tumor response rate as well [ 29 ]. The synergistic effect of IL-12 and IL-18 has also been investigated.…”

Reframing How Physical Activity Reduces The Incidence of Clinically-Diagnosed Cancers: Appraising Exercise-Induced Immuno-Modulation As An Integral Mechanism

“…Indeed, in the absence of altered thymic output – which is deemed largely insufficient for maintenance of naïve T cell frequency in older age ( 143 – 145 ) – it may be the case that naïve T cells are instead maintained extra-thymically via homeostatic turnover ( 143 ) chiefly via cytokines including IL-7 ( 104 ). There is evidence from human studies that recombinant IL-7 administration can increase the T cell repertoire ( 146 ), and this process may culminate in enhanced eradication of previously non-immunogenic tumours ( 147 ). Therefore, given that physical activity – and specifically skeletal muscle – is implicated in elevated levels of homeostatic cytokines such as IL-7, it may be the case that physical activity does indeed maintain naïve T cells ( 109 , 127 ), however more research is needed to confirm these observations.…”