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A Combination of Positive Tumor HLA-I and Negative PD-L1 Expression Provides an Immune Rejection Mechanism in Bladder Cancer

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Tumor human leukocyte antigen class I (HLA-I) expression plays an important role in T cell-mediated tumor rejection. Loss of HLA-I is associated with cancer progression and resistance to immunotherapy, including antibodies blocking programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling. Our objective was to analyze a correlation between HLA-I, tumor immune infiltration, and PD-L1/PD-1 axis in bladder cancer in association with the clinicopathologic features of patients.

Methods

We analyzed 85 cryopreserved bladder tumors by immunohistochemistry to investigate the expression of HLA-I, PD-L1, PD-1, CD3, CD8, and CXC chemokine receptor 4 (CXCR4). The results were correlated with tumor stage and other clinicopathologic variables of patients.

Results

We found a strong positive correlation between tumor HLA-I expression and infiltration with CD3+ and CD8 + T cells. PD-L1 expression was positive in 15.5% of tumors and heterogeneous in 40.5%, and was linked to a more advanced tumor stage. The majority of HLA-I-positive/heterogeneous tumors also expressed PD-L1 and PD-1, which were significantly correlated with each other and with lymphocyte infiltration. Interestingly, the analysis of the simultaneous expression of both markers revealed that 85.2% of tumors with a positive/heterogeneous HLA-I phenotype and negative for PD-L1 were mostly non-invasive, representing a ‘tumor rejection’ immune phenotype.

Conclusions

High tumor HLA-I expression with absence of PD-L1 provides bladder cancer with an immune rejection mechanism. Evaluation of PD-L1 and HLA-I together should be considered in bladder cancer and may provide a new predictive biomarker of tumor invasiveness and of the response to ‘immune checkpoint’ therapy.

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Acknowledgments

The authors would like to thank Svitlana Zinchenko for technical support, and Dr. Teresa Cabrera for the discussion and contribution to this work. The results of this work are part of the doctoral thesis of José Francisco Flores-Martín, within the Doctoral Program in Biomedicine at the University of Granada.

Funding

This work was supported by grants from the Spanish Institute of Health Carlos III (ISCIII, Instituto Carlos III) co-financed by the European Union (FEDER-Fondo Europeo de Desarrollo Regional) [PI12/02031, PI11/01022, PI11/01386, RETIC RD 06/020, PT13/0010/0039, PI14/01978, PI16/00752, PI17/00197] and by the Junta de Andalucía, Spain [Group CTS-143].

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Authors and Affiliations

  1. Instituto de Investigación Biosanitaria (ibs.GRANADA), Granada, Spain

    José Francisco Flores-Martín MD, Manuela Exposito-Ruiz PhD, Francisco Javier Carretero PhD, Teresa Rodriguez PhD, Francisco Ruiz-Cabello PhD, Federico Garrido MD, PhD, José Manuel Cózar-Olmo MD, PhD & Natalia Aptsiauri MD, PhD

  2. Unidad de Gestión Clínica de Urología, Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain

    José Francisco Flores-Martín MD & José Manuel Cózar-Olmo MD, PhD

  3. Unidad de Gestión Clínica de Urología, Complejo Hospitalario Universitario de Jaén, Jaén, Spain

    José Francisco Flores-Martín MD

  4. Departamento de Bioquímica, Biología Molecular e Inmunología III, Facultad de Medicina, Universidad de Granada, Granada, Spain

    Francisco Perea PhD, Francisco Javier Carretero PhD, Teresa Rodriguez PhD, Marina Villamediana MS, Francisco Ruiz-Cabello PhD, Federico Garrido MD, PhD & Natalia Aptsiauri MD, PhD

  5. Unidad de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Granada, Spain

    Marina Villamediana MS, Francisco Ruiz-Cabello PhD & Federico Garrido MD, PhD

  6. Fundación para la Investigación Biosanitaria de Andalucía Oriental (FIBAO), Granada, Spain

    Manuela Exposito-Ruiz PhD

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  1. José Francisco Flores-Martín MD
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  2. Francisco Perea PhD
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Correspondence to José Francisco Flores-Martín MD.

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Flores-Martín, J.F., Perea, F., Exposito-Ruiz, M. et al. A Combination of Positive Tumor HLA-I and Negative PD-L1 Expression Provides an Immune Rejection Mechanism in Bladder Cancer. Ann Surg Oncol 26, 2631–2639 (2019). https://doi.org/10.1245/s10434-019-07371-2

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