25P - Expression of immune checkpoint molecules in chronic myeloid leukemia at diagnosis and during tyrosine kinase inhibitor therapy

Date 20 November 2015
Event ESMO Symposium on Immuno-Oncology 2015
Session Welcome reception and general Poster viewing
Topics Leukaemia
Cancer Immunology and Immunotherapy
Presenter Olli Dufva
Citation Annals of Oncology (2015) 26 (suppl_8): 5-14. 10.1093/annonc/mdv514
Authors O. Dufva1, M. El Missiry1, H. Lähteenmäki1, S. Mustjoki2
  • 1Hematology Research Unit, HUCH Helsinki University Central Hospital, 00029 - Helsinki/FI
  • 2Hematology Research Unit, HUCH Helsinki University Central Hospital, 00290 - Helsinki/FI

Abstract

Aim

The potential of immune checkpoint inhibition in many hematological malignancies such as chronic myeloid leukemia (CML) has not been characterized in detail. Furthermore, differences in immune checkpoint-mediated immune suppression between peripheral blood (PB) and bone marrow (BM), where leukemia-initiating cells originate and persist during remission, are not known. Therefore, we aimed to evaluate the expression of immune checkpoint molecules both in PB and BM in chronic phase CML patients.

Methods

We performed multicolor flow cytometry on frozen PB and BM samples from 13 chronic phase CML patients (0, 1 and 6 months after the start of imatinib or dasatinib treatment) and 6 healthy controls. We analyzed the expression of PD-1, CTLA-4, LAG-3, ICOS and TIM-3 on T cells and PD-L1, PD-L2, CD80 and CD86 on antigen-presenting cells (APCs) and CD34+ cells. T cell receptor (TCR) repertoire was assayed by TCRB deep sequencing.

Results

At diagnosis, CD8+ T cells expressed higher levels of PD-1 in BM compared to PB (26.1 vs. 12.7 %, p = 0.001). PD-1 expression was highest in effector memory (TEM) and terminally differentiated (TEMRA) subpopulations, whereas naive and central memory (TCM) cells expressed only low levels of PD-1. TEM cells had markedly higher PD-1 expression in the BM compared to PB (51.0 vs. 38.2 %, p = 0.001). After 1 month of tyrosine kinase inhibitor (TKI) therapy, PD-1 expression on BM CD8+ T cells (also on TEM cells) decreased and persisted at a lower level after 6 months. APCs, such as myeloid type 1 dendritic cells expressed high levels of PD-L1 and CD86 in both PB and BM at diagnosis. During imatinib treatment, PD-L1 and CD86 were markedly reduced in PB but remained high in BM. PD-L1 was expressed also in leukemic CD34+ progenitor cells with a trend towards higher frequency in BM compared to PB. TCRB deep sequencing indicated increased clonality of the TCR repertoire in BM at diagnosis compared to healthy donors.

Conclusions

Both in CML and in healthy donors, BM and PB exhibit different immunological milieus in terms of expression of immune checkpoint molecules, such as increased PD-1 and PD-L1 in BM. During TKI therapy both PD-1 and PD-L1 levels decrease, suggesting at least partial reversal of immune cell exhaustion.

Clinical trial identification

Disclosure

S. Mustjoki: Honoraria and research funding from BMS, Novartis and Pfizer. All other authors have declared no conflicts of interest.