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The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients

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Abstract

Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients. This effect could not be ascribed to Syk-inhibition given that we show that T cells from CLL patients do not express Syk protein. Interestingly, ζ-chain-associated protein kinase (ZAP)-70 phosphorylation was diminished by both inhibitors upon TCR stimulation on T cells. In addition, we found that both agents reduced macrophage-mediated phagocytosis of rituximab-coated CLL cells. Overall, these results suggest that in CLL patients treated with R406 or GS-9973 T cell functions, as well as macrophage-mediated anti-tumor activity of rituximab, might be impaired. The potential consequences for CLL-treated patients are discussed.

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Abbreviations

BCR:

B cell receptor

Btk:

Bruton’s tyrosine kinase

CD40L:

CD40 ligand

CFSE:

Carboxyfluorescein succinimidyl ester

CLL:

Chronic lymphocytic leukemia

ECL:

Enhanced chemiluminescence

Flt3:

Fms-like tyrosine kinase 3

Lck:

Lymphocyte-specific protein tyrosine kinase

M-CSF:

Macrophage colony-stimulating factor

Rx:

Rituximab

pAb:

Polyclonal antibodies

PVDF:

Polyvinylidene difluoride

SEM:

Standard error of the mean

Syk:

Spleen tyrosine kinase

Th:

T helper

ZAP-70 :

ζ-chain-associated protein kinase-70

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Acknowledgements

This work was supported by grants from Fondo para la Investigación Científica y Tecnológica (PICT 1074/2013 and PICT 1310/2012), Ministry of Science, Technology and Innovation, Argentina. We are indebted to Beatriz Loria, María Tejeda and Federico Fuentes for their technical assistance.

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Authors and Affiliations

  1. Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Buenos Aires, Argentina

    Ana Colado, María Belén Almejún, Enrique Podaza, Denise Risnik, Esteban Enrique Elías, Mirta Giordano, Romina Gamberale & Mercedes Borge

  2. Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina

    María Belén Almejún

  3. Servicio de Patología Molecular, Instituto de Investigaciones Hematológicas-ANM, Buenos Aires, Argentina

    Carmen Stanganelli

  4. Laboratorio de Genética de Neoplasias Linfoides, IMEX-CONICET-ANM, Buenos Aires, Argentina

    Patricia Dos Santos & Irma Slavutsky

  5. Departamento de Hematología, Sanatorio Julio Méndez, Buenos Aires, Argentina

    Horacio Fernández Grecco & María Cabrejo

  6. Sección de Hematología, Hospital General de Agudos Dr. Teodoro Álvarez, Buenos Aires, Argentina

    Raimundo Fernando Bezares

  7. Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

    Mirta Giordano, Romina Gamberale & Mercedes Borge

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  1. Ana Colado
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  2. María Belén Almejún
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  3. Enrique Podaza
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  9. Horacio Fernández Grecco
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  10. María Cabrejo
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  11. Raimundo Fernando Bezares
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  12. Mirta Giordano
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  13. Romina Gamberale
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  14. Mercedes Borge
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Correspondence to Mercedes Borge.

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Conflict of interest

Romina Gamberale had received compensation as speaker for Janssen and Bristol-Myers Squibb, as speaker and consultant for Roche, and as a member of the advisory board of AbbVie. Raimundo Fernando Bezares had received compensation as speaker from Novartis, Varifarma and Roche. All the other authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Colado, A., Almejún, M.B., Podaza, E. et al. The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients. Cancer Immunol Immunother 66, 461–473 (2017). https://doi.org/10.1007/s00262-016-1946-y

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