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Interaction of Breast Cancer and Insulin Resistance on PD1 and TIM3 Expression in Peripheral Blood CD8 T Cells

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Pathology & Oncology Research

Abstract

Epidemiological evidence points to a link between insulin resistance (IR) and breast cancer (BrCA). Insulin plays a role in CD8+ T cells (CD8T) differentiation and function and affects adipocytokines levels. CD8T activity in BrCA is associated with favorable outcome; while PD1 and TIM3 are markers of CD8T exhaustion and play critical roles in the negative regulation of T cell responses. Patients with (BrCA) have high expression levels of PD1 on circulating. Therefore, we hypothesized that BrCA and IR could affect PD1 and/or TIM3 expression on circulating CD8T. We determine PD1 and TIM3 expression on CD8T and analyze the relationship of CD8T phenotype with serum insulin and plasma adipocytokines levels in the different groups. We enrolled four groups of treatment-naive patients: women without neoplasms (Neo-)/without IR (IR-), Neo−/with IR (IR+), BrCa/IR- and BrCa/IR+. We found interactions between BrCA and IR with respect to TIM3 on naïve and central memory (CM) CD8T subsets. Furthermore, BrCA had a greater PD1 + TIM3- CD8T frequency in CD8T subsets than Neo-. IR+ presented a significantly lower PD1 + TIM3- frequency in CD8T subsets compare to Non-IR. In addition, we found a negative correlation between insulin levels, HOMA and frequency of PD1 + TIM3- in CD8T and a positive correlation between adiponectin levels and the frequency PD1 + TIM3- in CD8T. The increased expression of PD1 on different subsets of CD8T from BrCa patients is consistent with immunological tolerance, whereas IR has a contrary effect. IR could have a deleterious role in the activation of CD8T that can be relevant to new BrCa immunotherapy.

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Acknowledgments

Miriam Victoria Martín Manzo is a doctoral student from Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM) and received fellowship 243633 from Consejo Nacional de Ciencia y Tecnología (CONACYT). This paper is part of her doctoral thesis.

The authors wish to thank Dra. Concepción Agundis-Mata and Dra. Gabriela Gutiérrez for general laboratory facilities, as well as PhD Enrique Ortega, PhD Erasmo Martínez and PhD Ali Pereyra for critical review. They highly appreciate the help of M.Sc. Carlos Castellanos Barba and the LabNalCit-UNAM (CONACYT). In addition, they thank to Neyla Baltazar from Hospital General de México “Dr. Eduardo Liceaga” for blood sample collection and metabolic parameters determination.

Funding

This study was funded by Consejo Nacional de Ciencia y Tecnología FOSISS-233471, SEP-134341 and internal resources of the “Programa Institucional de Cáncer de Mama” (IIB). Work in SM’s lab is supported by NHI-R01A1119131.

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Authors and Affiliations

  1. Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, México

    Miriam Victoria Martín-Manzo

  2. HIPAM, Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, México

    Miriam Victoria Martín-Manzo, David Kershenobich & Joselin Hernandez

  3. Servicio de Oncología, Hospital General de México Dr. Eduardo Liceaga, Ciudad de México, México

    Carlos Lara

  4. Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México

    Cruz Vargas-de-Leon

  5. Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

    Julio Carrero

  6. Departamento de Genética, Hospital General de México Dr. Eduardo Liceaga, Ciudad de México, México

    Gloria Queipo & Miguel Fonseca-Sanchez

  7. Facultad de Medicina Universidad Nacional Autónoma de México, Ciudad de México, México

    Gloria Queipo

  8. Red de Apoyo a la Investigación (RAI), CIC-Universidad Nacional Autónoma de México, Ciudad de México, Mexico

    Nancy R. Mejia-Dominguez

  9. Dirección General, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico

    David Kershenobich

  10. South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Edinburg, TX, USA

    Srinivas Mummidi & Joselin Hernandez

  11. Programa Institucional de Cáncer de Mama, Departamento de Toxicología Ambiental y Medicina Genómica, IIB, Universidad Nacional Autónoma de México, Departamento de Bioquímica INCMNSZ; Centro de Cáncer, CM AB, Ciudad de México, Mexico

    Alejandro Zentella-Dehesa

  12. Research Deparment, Universidad Mexico Americana del Norte, Reynosa, Mexico

    Joselin Hernandez

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  1. Miriam Victoria Martín-Manzo
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Correspondence to Joselin Hernandez.

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Ethical Approval

The study was approved by the ethical and research committees of the General ospital of Mexico “Dr. Eduardo Liceaga” (DI/15/UME/03/47 and DI/12/III/4/30). 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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Martín-Manzo, M.V., Lara, C., Vargas-de-Leon, C. et al. Interaction of Breast Cancer and Insulin Resistance on PD1 and TIM3 Expression in Peripheral Blood CD8 T Cells. Pathol. Oncol. Res. 25, 1233–1243 (2019). https://doi.org/10.1007/s12253-019-00610-7

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