PF401 IMMUNE SYSTEM AND CHRONIC MYELOID LEUKEMIA: THE IMPACT OF TYROSINE KINASE INHIBITORS
Authors: Alves R.S. , McArdle S.E. , Vadakekolathu J. , Gonçalves A.C. , Freitas‐Tavares P. , Pereira A. , Almeida A.M. , Sarmento‐Ribeiro A.B. , Rutella S. 
Published: June 2019

Background:

During carcinogenesis, tumor cells alter their immunogenicity in an attempt to escape surveillance of the immune system (SI). This surveillance process involves NK cells and T lymphocytes, and various immunological factors, in order to combat tumor progression. By contrast, tumor cells recruit immunosuppressive cells [like regulatory T‐cells (Treg), myeloid‐derived suppressor cells (MDSC)] and secrete factors such as PD‐L1. Targeted therapies, such as Imatinib (Ima), have off‐target effects that may influence immune function. Imatinib has been shown to modulate multiple cell types involved in anti‐cancer immune surveillance, with potentially detrimental as well as favorable outcomes. The therapeutic efficacy of Ima and other tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has radically changed the course of this disease. The current challenge is to predict which patients will develop resistance to TKIs and who will need another therapeutic approach. The deepening in knowledge about immunological mechanisms in CML and their relationship with tumor promotion are essential for the development of immunotherapy.

Aims:

The aim of this study was to characterize the different population of the immune system in patients with CML under treatment.

Methods:

For this purpose, 41 patients with CML (33 treated with TKI and 8 with TKI+IFN‐α) and 20 controls were included in the study. In peripheral blood samples, the different populations of SI (Overview of Immune System (OVIS) panel, Treg and MDSC) and PD‐1 expression were evaluated by flow cytometry. The immunological profile was evaluated by RNA Pan‐Cancer Immune Profiling Panel using the NanoString platform. Statistical analysis was performed considering a level of significance of 95%.

Results:

Patients on combined therapy (TKI+IFN‐α) had lower numbers of lymphocytes, especially T lymphocytes [838/μL (95% CI: 594 – 1,182)] compared with controls [1,500/μL (95% CI: 1,207 – 1,865), p = 0.017]. In addition, these patients also presented a higher percentage of Treg (≈9%) and CD4+/PD‐1+ cells (≈2%). When we evaluated the MDSC compartment, patients treated with TKI only had more Mo‐MDSC (≈12.5%) whereas those treated with TKI plus IFN‐α have more Gr‐MDSC (≈20%), compared to the controls (p≤0.05). Inside the group of patients treated with TKI in monotherapy, we observed that patients treated with 2nd generation TKIs had lower percentage of CD4+ Treg (≈4%) and Gr‐MDSC (≈4%) compared to patients under Ima treatment (CD4+ Treg ≈6% and Gr‐MDSC ≈8%), but higher levels of CD4+ cells positive for PD‐1 (≈2%). The analysis of the transcriptome allowed the recognition of a gene expression signature that identified the only patient without response to therapy.

Summary/Conclusion:

Our results suggest that TKIs have an impact on immune system and when combined with IFN‐α appears to be associated with increased immunosuppression. However, to confirm our results more patients need to be included in the study, especially at diagnosis.

The work was supported by John and Lucille van Geest Foundation, FMUC, CIMAGO (Project 18/12) and FCT (SFRH/BD/51994/2012).