Identification of a highly suppressive Treg subset associated with immunotherapy response
 
Romano S¹, D'Arrigo P¹, Troiani T², Rea A¹, Tufano M¹, Giunta EF², Matarese G^1,3, Procaccini C³, Novizio N¹, Vigorito V¹, Faicchia D³, Argenziano G⁴, Romano MF^1
1DMMBM Federico II Naples, Italy. ²Oncologia Medica Università L Vanvitelli.³IEOS, CNR, Naples, Italy.⁴Dermatology Unit, Università L Vanvitelli, Naples Italy
  
Melanoma often exploits Treg to avoid immune attack. Treg is a heterogeneous population with respect to immunosuppressive capability. Lymphocytes are particularly rich in FKBP51 (encoded by FKBP5 gene), known as the receptor for FK506. Melanoma aberrantly expresses this protein, which sustains resistance and invasion. Melanoma/immune cell interaction, through PD-L1/PD1, bidirectionally generates FKBP5 splicing inducing a lower molecular weight form termed FKBP51s. In 64 advanced melanoma patient PBMCs, we found that FKBP51s marked a Treg subset that correlated to anti-CTLA4 response. More precisely, a Treg FKBP51s⁺ count <1% was associated with unresponsiveness (normal donor-range 0.1-0.7%). Aim of the present study was to assess the role of Treg FKBP51s+ as potential biomarker of response in a different cohort of patients treated with anti-PD1. In addition, the suppressive potential of Treg FKBP51s+ in comparison with that of Treg FKBP51s- is investigated. To date, we have outcomes of 11 patients. For each patient, we have collected up to 10 blood samples, at T0 and before each treatment, to monitor Tregs. In 5 responder patients, Treg FKBP51s+ was >1.2 and < 4.8; in 5 non responder patients, the count was >0.04 and < 0.8 After a transient increase following the first administration, the count decreased to 0.3+0.2% in responder patients. Interestingly, a patient with count = 0.7% developed autoimmune side effects that led to therapy discontinuation. Resolution of side effects was accompanied by a value increase to 9.9%; anti-PD1 re-administration was then successful. In vitro iTreg generation showed that FKBP51s was upregulated in Treg CD25^high, Ki67^high and p70S6k^high , corresponding to a highly metabolically active profile with strong suppressive capability. In conclusion, melanoma patients that benefit from immune checkpoint targeted therapy are recognizable by an expansion of a Treg subset which is marked by FKBP51s, a splicing protein isoform generated by triggering of surface antigens (PD-L1, PD1), abundantly expressed on highly suppressive Tregs.