Clinical Features of Cutaneous T-Cell Lymphoma and the Application of Anti-PD-1 Antibodies in Relapsed /Refractory Patients

Background: Primary cutaneous T-cell lymphoma (CTCL) is a rare type of extranodal non-Hodgkin's lymphoma that primarily affects the skin, which has been insufficiently reported to date. It represents a heterogenous group of disease with a complex immunological background, and are characterized by high progression and relapse rates. Currently, immune checkpoint inhibitors, such as antibodies against PD-1 (programmed cell death 1), are considered as a promising therapy for relapsed /refractory (R/R) CTCL. It is urgently needed to characterize the tumor microenvironment (TME) in the disease and better predict the clinical response to anti-PD-1 therapy. Methods: Demographic, clinical characteristics, and incidence data from the Surveillance, Epidemiology and End Results (SEER) database were screened for patients with CTCL. Meanwhile, we conducted a retrospective analysis of 64 patients diagnosed with CTCL at Tianjin Medical University Cancer Institute and Hospital (TMUCIH). Spatial enhanced resolution omics sequencing (Stereo-seq) was performed on FFPE samples at different time from one patient diagnosed with primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (PC-AECTCL). Results: We identified 6911 patients diagnosed with CTCL between 2000 to 2021 from SEER database. The overall incidence was 8 per million and ranged from 7 to 9 per million people in the last 20 years. There was a male predominance with the rates of 9 for males and 6 for females. It mostly affects elderly people with a median age at diagnosis of 60 years. The most common subtype was mycosis fungoides [MF; n = 3411 (49.4%)], followed by primary cutaneous T-cell lymphomas, NOS [CTCL-NOS; n = 2277 (32.9%)] and primary cutaneous anaplastic large cell lymphoma [PCALCL; n = 982 (14.2%)]. The remaining subtypes accounted for less than 5% of CTCLs including Sézary syndrome [SS; n = 161 (2.3%)], subcutaneous panniculitis-like T-cell lymphoma [SPTCL; n = 43 (0.6%)], and primary Cutaneous γ/δ T cell lymphoma [PCGD-TCL; n = 37 (0.5%)]. Other rare subtypes are not recorded in the SEER database. Survival analysis indicated that the 5-year overall survival (OS) rate of MF, CTCL-NOS, PCALCL and SPTCL were 82.8%, 71.4%, 74.4%, 80.4%, respectively, while SS and PCGD-TCL had more unfavorable prognosis, with 5-year OS rate of 40.8% and 51.4%. It was shown age>60, male, advanced stage, and primary sites >1 were associated with worse OS and disease specific survival in univariate and multivariate analysis. In addition, we analyzed the treatment data of CTCL patients from TMUCIH. For patients with limited-stage, 6 patients chose to “watch and wait”, 5 received surgery, radiotherapy, or other skin-directed therapies, and 43 patients received systemic chemotherapy (mostly CHOP/CHOPE) as initial treatment. But advanced patients were mostly treated with combined modality therapy. A total of 4 patients underwent autologous stem cell transplantation. However, 40.6% (n = 26) of patients experienced disease progression or recurrence, and of which 14 patients received 3 or more lines of treatment. Notably, there were 6 patients treated with anti-PD-1 antibody-based therapy, with 66.7% achieving a response (2 complete remission, 2 partial remission). To deeply understand the molecular events underlying disease progression and identify the possible factors that affect the efficacy of immunotherapy, we applied Stereo-seq to one of the patients who achieved CR after anti-PD-1 therapy and maintained disease-free survival for more than 3 years. We identified spatial localization of different cell types and spatial expression patterns within the TME of PC-AECTCL tissues. The tumor cell cluster shows highly expression of PD-L1, and immune cell infiltrate of the skin microenvironment demonstrates an immune-suppressive profile. Conclusions: Overall, our study analyzed the epidemiology of CTCL and supported the efficacy of anti-PD-1 antibodies in R/R CTCL through real-world data. Spatial transcriptomics help enhance the understanding of the TME in CTCL and further provided guidance for immunotherapy.