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The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy

SIMPLE SUMMARY: Combining chemoradiotherapy with immunotherapy is one of the main milestones in cancer treatment. The optimal sequence to ensure the effectiveness of the treatment is unknown. We investigated the kinetics of FMS-related tyrosine kinase 3 ligand (Flt-3L), a multi-potential haemopoieti...

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Autores principales: Kuncman, Łukasz, Orzechowska, Magdalena, Stawiski, Konrad, Masłowski, Michał, Ciążyńska, Magdalena, Gottwald, Leszek, Milecki, Tomasz, Fijuth, Jacek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9405787/
https://www.ncbi.nlm.nih.gov/pubmed/36010838
http://dx.doi.org/10.3390/cancers14163844
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author Kuncman, Łukasz
Orzechowska, Magdalena
Stawiski, Konrad
Masłowski, Michał
Ciążyńska, Magdalena
Gottwald, Leszek
Milecki, Tomasz
Fijuth, Jacek
author_facet Kuncman, Łukasz
Orzechowska, Magdalena
Stawiski, Konrad
Masłowski, Michał
Ciążyńska, Magdalena
Gottwald, Leszek
Milecki, Tomasz
Fijuth, Jacek
author_sort Kuncman, Łukasz
collection PubMed
description SIMPLE SUMMARY: Combining chemoradiotherapy with immunotherapy is one of the main milestones in cancer treatment. The optimal sequence to ensure the effectiveness of the treatment is unknown. We investigated the kinetics of FMS-related tyrosine kinase 3 ligand (Flt-3L), a multi-potential haemopoietic protein, and observed an increase in its concentration following bone marrow-damaging irradiation. At the same time, Flt-3L is an important regulating factor of dendritic cells, which are essential for the immune effect of lymphocytes. We observed an increase in Flt-3L levels in the first two weeks of treatment with no further increase during chemoradiotherapy. Our model explains the early variability of Flt-3L, which was related to the irradiation dose in active bone marrow and the subsequent lymphopenia. Our results argue for the earlier initiation of immunotherapy when the concentration of Flt-3L is high and no lymphopenia has yet occurred. ABSTRACT: The optimal sequence of chemoradiotherapy with immunotherapy is still not established. The patient’s immune status may play a role in determining this order. We aim to determine the kinetics of a multi-potential haemopoietic factor FMS-related tyrosine kinase 3 ligand (Flt-3L) during chemoradiotherapy. Our pilot, a single arm prospective study, enrolled patients with rectal cancer who qualified for neoadjuvant chemoradiotherapy. Blood samples for Flt-3L were collected before and every second week of chemoradiotherapy for a complete blood count every week. The kinetics of Flt-3L were assessed using Friedman’s ANOVA. A multiple factor analysis (MFA) was performed to find relevant factors affecting levels of serum Flt-3L during chemoradiotherapy. FactoMineR and factoextra R packages were used for analysis. In the 33 patients enrolled, the level of Flt-3L increased from the second week and remained elevated until the end of treatment (p < 0.01). All patients experienced Grade ≥2 lymphopenia with a nadir detected mostly in the 5/6th week. MFA revealed the spatial partitioning of patients among the first and second dimensions (explained by 38.49% and 23.14% variance). The distribution along these dimensions represents the magnitude of early changes of Flt-3L. Patients with the lowest values of Flt-3L change showed the highest lymphocyte nadirs and lowest dose/volume parameters of active bone marrow. Our hypothesis-generating study supports the concept of early initiation of immuno-therapy when the concentration of Flt-3L is high and no lymphopenia has yet occurred.
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spelling pubmed-94057872022-08-26 The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy Kuncman, Łukasz Orzechowska, Magdalena Stawiski, Konrad Masłowski, Michał Ciążyńska, Magdalena Gottwald, Leszek Milecki, Tomasz Fijuth, Jacek Cancers (Basel) Article SIMPLE SUMMARY: Combining chemoradiotherapy with immunotherapy is one of the main milestones in cancer treatment. The optimal sequence to ensure the effectiveness of the treatment is unknown. We investigated the kinetics of FMS-related tyrosine kinase 3 ligand (Flt-3L), a multi-potential haemopoietic protein, and observed an increase in its concentration following bone marrow-damaging irradiation. At the same time, Flt-3L is an important regulating factor of dendritic cells, which are essential for the immune effect of lymphocytes. We observed an increase in Flt-3L levels in the first two weeks of treatment with no further increase during chemoradiotherapy. Our model explains the early variability of Flt-3L, which was related to the irradiation dose in active bone marrow and the subsequent lymphopenia. Our results argue for the earlier initiation of immunotherapy when the concentration of Flt-3L is high and no lymphopenia has yet occurred. ABSTRACT: The optimal sequence of chemoradiotherapy with immunotherapy is still not established. The patient’s immune status may play a role in determining this order. We aim to determine the kinetics of a multi-potential haemopoietic factor FMS-related tyrosine kinase 3 ligand (Flt-3L) during chemoradiotherapy. Our pilot, a single arm prospective study, enrolled patients with rectal cancer who qualified for neoadjuvant chemoradiotherapy. Blood samples for Flt-3L were collected before and every second week of chemoradiotherapy for a complete blood count every week. The kinetics of Flt-3L were assessed using Friedman’s ANOVA. A multiple factor analysis (MFA) was performed to find relevant factors affecting levels of serum Flt-3L during chemoradiotherapy. FactoMineR and factoextra R packages were used for analysis. In the 33 patients enrolled, the level of Flt-3L increased from the second week and remained elevated until the end of treatment (p < 0.01). All patients experienced Grade ≥2 lymphopenia with a nadir detected mostly in the 5/6th week. MFA revealed the spatial partitioning of patients among the first and second dimensions (explained by 38.49% and 23.14% variance). The distribution along these dimensions represents the magnitude of early changes of Flt-3L. Patients with the lowest values of Flt-3L change showed the highest lymphocyte nadirs and lowest dose/volume parameters of active bone marrow. Our hypothesis-generating study supports the concept of early initiation of immuno-therapy when the concentration of Flt-3L is high and no lymphopenia has yet occurred. MDPI 2022-08-09 /pmc/articles/PMC9405787/ /pubmed/36010838 http://dx.doi.org/10.3390/cancers14163844 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kuncman, Łukasz
Orzechowska, Magdalena
Stawiski, Konrad
Masłowski, Michał
Ciążyńska, Magdalena
Gottwald, Leszek
Milecki, Tomasz
Fijuth, Jacek
The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy
title The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy
title_full The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy
title_fullStr The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy
title_full_unstemmed The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy
title_short The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy
title_sort kinetics of fms-related tyrosine kinase 3 ligand (flt-3l) during chemoradiotherapy suggests a potential gain from the earlier initiation of immunotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9405787/
https://www.ncbi.nlm.nih.gov/pubmed/36010838
http://dx.doi.org/10.3390/cancers14163844
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