Abstract 3965: A cytolytic effector CD8+ T cell response is associated with remission in adult T-cell leukemia/lymphoma

Abstract Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare blood cancer that develops in 3-5% of human T-lymphotropic virus-1 (HTLV1) carriers when the combination of viral oncoproteins and somatic mutations lead to malignant transformation of HTLV1 infected CD4+ T cells. ATLL has the worst overall survival among peripheral T cell lymphomas and remains a fatal disease despite efforts to improve outcomes over the last 35 years. First-line combination chemotherapy rarely achieves a durable response and two immune-modulating treatments (α-CCR4 and α-PD-1 monoclonal antibodies) failed in clinical trials. These findings highlight an urgent need to improve our understanding of the functional state of host immunity in ATLL patients. A host immune response against HTLV1 is pivotal in preventing ATLL development. Malignant ATLL cells can escape immune surveillance by preventing antigen presentation and engaging immune checkpoints. The prospect of an ATLL clone inducing systemic suppression was suggested in the literature but has not been directly examined. Furthermore, HTLV1-specific CD8+ cytotoxic T lymphocytes (CTLs) play an important role during viral latency, yet it remains unknown if they play a clinically relevant role during ATLL treatment. Methodology: In this work, we hypothesized that malignant ATLL cells will exhibit a suppressive immune phenotype and that effective therapeutic interventions will augment anti-ATLL CTLs to promote durable remission. We implemented an immune profiling approach to analyze PBMC samples from ATLL patients. Specifically, we developed a powerful 30-marker spectral flow panel to discriminate malignant ATLL cells from non-transformed lymphocytes (T, B, and NK cells) and monitor the expression of key transcription factors and markers associated with proliferation, cytolysis, and exhaustion. We analyzed diagnostic samples from the Montefiore-Einstein ATLL Biobank and samples collected during a phase 2 clinical trial aimed to assess the efficacy of a promising Belinostat/Zidovudine/Interferon-α combination therapy against ATLL (NCT02737046). Results: Our findings reveal that malignant ATLL cells exhibit an immune phenotype associated with robust immunosuppression and yet distinct from other suppressive immune cells (i. e. , regulatory T cells). Additionally, we discovered that ATLL patient samples contained a unique population of phenotypically exhausted CD8+ T cells, the proportion of which was drastically reduced in patients under remission. Remarkably, a decrease in this exhausted subset correlated with the expansion of highly cytolytic CD8+ CTLs. Conclusion: Altogether, our findings suggest that ATLL cells may drive CD8+ CTLs into exhaustion to achieve immune evasion and that a robust anti-ATLL CTL response actively contributes to a remission state. Citation Format: Erik Guillen, Eric Liu, Yanhua Wang, Aditi Shastri, Alejandro Sica, Amit Verma, Xingxing Zhang, Juan Carlos Ramos, Hilda Ye, Gregoire Lauvau. A cytolytic effector CD8+ T cell response is associated with remission in adult T-cell leukemia/lymphoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3965.