Exhaustion of CD8(+) central memory responder T cell differentiation provokes non-melanoma skin cancer in elderly kidney transplant recipients

INTRODUCTION: Immunosuppressive therapy prevents graft rejection but increases the risk of non-melanoma skin cancer (NMSC), especially in elderly kidney transplant recipients (KTR). METHODS: In this study, we separately investigated the differentiation of CD8(+) regulatory T cells (Tregs) and responder T cells (Tresps) between healthy KTR without NMSC, KTR developing de-novo NMSC within two years after the enrolment, and KTR with NMSC at the time of enrolment. Antigen-unexperienced CCR7(+)CD45RA(+)CD31(+) recent thymic emigrant (RTE) cells differentiate via CD45RA(-)CD31(+) memory (CD31(+) memory) cells, via resting mature naïve (MN) cells or via direct proliferation into CD45RA(-)CD31(-) memory (CD31(-) memory) cells, consisting of both CCR7(+)CD45RA(-) central memory (CM) and CCR7(-)CD45RA(-) effector memory (EM) cells. RESULTS: We found that both RTE Treg and Tresp differentiation via CD31(+) memory Tregs/Tresps was age-independently increased in KTR, who developed de novo NMSC during the follow-up period, causing abundant CM Treg/Tresp production, which may be crucial for cancer immunity. These changes favored a strongly increased CD8(+) Treg/Tresp ratio, suggesting this ratio as a reliable marker for de-novo NMSC development in KTR. However, with age, this differentiation was replaced by increased conversion of resting MN Tregs/Tresps into CM Tregs/Tresps, which exhausted for Tresps but not for Tregs. In KTR with already existing NMSC at enrolment, differentiation was maintained via conversion and proliferation of resting MN Tregs/Tresps, which however increasingly exhausted with age, especially for Tresps. This resulted in a strong accumulation of terminally differentiated effector memory (TEMRA) Tresps in elderly individuals. Patients with NMSC recurrence showed increased proliferation of resting MN Tregs/Tresps into EM Tregs/Tresps, which tended to exhaust more rapidly, particularly for Tresps, than in patients without NMSC recurrence. DISCUSSION: In conclusion, we provide evidence that immunosuppressive therapy inhibits differentiation of CD8(+) Tregs more than that of CD8(+) Tresps, resulting in an exhausted Tresp profile, thus providing a possible therapeutic approach to improve poor cancer immunity in elderly KTR.