Intrinsically altered lung‐resident γδT cells control lung melanoma by producing interleukin‐17A in the elderly

Abstract

Cancer is an age-associated disease, potentially related to the altered immune system of elderly individuals. However, cancer has gradually decreased incidence in the eldest globally such as the most common lung cancer, the mechanisms of which remain to be elucidated. In this study, it was found that the number of lung-resident γδT cells was significantly increased with altered gene expression in aged mice (20-24 months) versus young mice (10-16 weeks). Aged lung Vγ4 + and Vγ6 + γδT cells predominantly produced interleukin-17A (IL-17A), resulting in increased levels in the serum and lungs. Moreover, the aged mice exhibited smaller tumors and reduced numbers of tumor foci in the lungs after challenge with intravenous injection of B16/F10 melanoma cells compared with the young mice. Aged lung Vγ4 + and Vγ6 + γδT cells were highly cytotoxic to B16/F10 melanoma cells with higher expression levels of CD103.The markedly longer survival of the challenged aged mice was dependent on γδT17 cells, since neutralization of IL-17A or depletion of indicated γδT cells significantly shortened the survival time. Consistently, supplementation of IL-17A significantly enhanced the survival time of young mice with lung melanoma. Furthermore, the antitumor activity of aged lung γδT17 cells was not affected by alterations in the load and composition of commensal microbiota, as demonstrated through co-housing of the aged and young mice. Intrinsically altered lung γδT17 cells underlying age-dependent changes control lung melanoma, which will help to better understand the lung cancer progression in the elderly and the potential use of γδT17 cells in anti-tumor immunotherapy.

Evolved to protect, designed to destroy: IL‐17‐producing γδ T cells in infection, inflammation, and cancer

“…A similar contradiction is evident when the B16-F10 melanoma model was used to assess lung antitumor responses in aged mice. Although initial data showed that in aged mice γδT17 cells contributed to pathogenicity in the Lewis lung carcinoma transplantable model [123], the opposite was demonstrated when B16-F10 cells were used [132]. In a completely different setting, the protective effects of BCG vaccination against bladder cancer in mice were shown to be dependent on a productive γδT17 response [133].…”

The accumulation of Vγ4 T cells with aging is associated with an increased adaptive Vγ4 T cell response after foodborne Listeria monocytogenes infection of mice

“…γδT 17 cell accumulation has been reported in both lymphoid and mucosal tissues of aged mice [ 29 , 30 ]. This led us to assess whether the age-dependent increase in CD44 hi CD27 neg Vγ1.1 neg Vγ2 neg γδ T cells was restricted to the MLN.…”

“…Observational studies reported an overall decrease in γδ T cell numbers [ 24 – 26 ], a shift from a naïve to a late differentiated phenotype, and a decreased proliferative capacity of human circulating γδ T cells in older individuals, although circulating Vδ2 + T cells seem more resistant to immunosenescence than other γδ T cell subsets [ 26 , 27 ]. More recently, an age-dependent accumulation of IL-17A-producing γδ T (γδT 17 ) cells has been shown in mouse adipose tissues [ 28 ], lungs [ 29 ] and lymphoid tissues [ 30 ]. As such, some γδ T cell subsets may be more resistant to the deleterious effects of aging and may provide exploitable anti-infectious functions in aged hosts or represent targetable cellular subsets in inflammatory diseases.…”

The role of γδ T17 cells in cardiovascular disease

“…On the other hand, the antitumor function of γδ T17 cells has also been reported. Aging induces γδ T cells to produce IL‐17A, which plays a key role in the development of resistance to lung melanoma in elderly mice 226 . Infiltration of γδ T17 cells was observed in epithelial tumors after chemotherapy.…”