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Danger signaling to NK cells in AML
Table 2. Univariate Cox proportional hazard analysis. RFS
Table 3. Multivariate Cox proportional hazard analysis. RFS
Variable
Age
Sex
Peripheral blast counts HSCT
Ecto-CRT+ blasts (%) KLRK1 expression NKG2D+ NK cells (%)
HR (95% CI)
1.02 (0.99-1.04)
0.79 (0.44-1.43) 1.00 (0.99-1.01) 0.76 (0.40-1.44) 0.99 (0.98-1.00) 0.80 (0.53-1.19) 0.96 (0.92-1.01)
P
0.19
0.45 0.26 0.40 0.22 0.27 0.13
Variable
Age
Sex
Peripheral blast counts HSCT
Ecto-CRT+ blasts (%) KLRK1 expression NKG2D+ NK cells (%)
HR (95% CI)
1.07 (1.01-1.13)
1.34 (0.50-3.60) 1.00 (0.98-1.02) 0.62 (0.21-1.83) 0.98 (0.96-1.00) 0.69 (0.44-1.07) 0.95 (0.90-1.01)
P
0.007*
0.55 0.71 0.39 0.10 0.10 0.11
CI, 95% confidence interval; HR, hazard ratio; *p< 0.05; RFS, relapse-free survival.
this possibility. Indeed, in vivo application of C1498 AML cells engineered to constitutively expose CRT on their sur- face elicited an accumulation of highly functional NK cells and CD4+ and CD8+ T cells in mouse tumors and/or spleen (Figure 4B-D).
Finally, both CRT exposure on malignant blasts and NK cell-related marker NKG2D were associated with improved RFS amongst AML patients (Figure 5A-C), corroborating previously published data.10,34 Combinatorial assessment of the prognostic value of these parameters identified signifi- cantly prolonged RFS in KLRK1HiCRTHi and NKG2DHiCRTHi subgroup of patients (Figure 5D-E). However, these findings could not be confirmed using univariate and multivariate Cox proportional hazard analysis, potentially reflecting a limited follow-up period, the small size of the patient cohort, disease subset and/or inter-patient heterogeneity. Thus, the precise prognostic value of CRT exposure on AML blasts and NKGD2 levels on NK cells remains to be validated in independent patient series.
Taken together, our results support the association of CRT with enhanced activation of the innate and adap- tive anticancer immunity. Parallel assessment of CRT exposure on malignant blasts and immune cell parame- ters, such as NK-cell markers, may provide prognostic
CI, 95% confidence interval; HR, hazard ratio; *p< 0.05; RFS, relapse-free survival.
information and have therapeutic relevance for AML patients in the future.
Funding
This study was exclusively sponsored by Sotio, Prague, Czech Republic.
Acknowledgments
The authors thank Anna Fialova for her valuable help with statistical analysis and to Jana Bieblova for help with FACS and ELISA analysis. LG is supported by a Breakthrough Level 2 grant from the US Department of Defense (DoD), Breast Cancer Research Program (BRCP) (#BC180476P1), by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177, PI: Formenti) from the Stand Up to Cancer (SU2C), by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukemia and Lymphoma Society (LLS), by a startup grant from the Dept. of Radiation Oncology at Weill Cornell Medicine (New York, NY, USA), by a Rapid Response Grant from the Functional Genomics Initiative (York, NY, USA), by industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (York, NY, USA), and by donations from Phosplatin (York, NY, USA), the Luke Heller TECPR2 Foundation (Boston, USA) and Sotio a.s. (Prague, Czech Republic).
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