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Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma

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Abstract

Background

The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.

Objective

We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).

Patients and Methods

Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR−) and CTL (CD8+CD4−) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15−), polymorphonuclear (PMN)-MDSC (CD14−CD15+), and immature (I)-MDSC (CD14−CD15−). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.

Results

Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette–Guérin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.

Conclusions

Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.

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Author information

Author notes

  1. Petros Grivas

    Present address: Department of Medicine, Division of Oncology, University of Washington and Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA, USA

  2. Moshe Ornstein and Petros Grivas share senior authorship for this paper.

Authors and Affiliations

  1. Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Alice Tzeng

  2. Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    C. Marcela Diaz-Montero, Patricia A. Rayman, Jin S. Kim, Paul G. Pavicic Jr & James H. Finke

  3. Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Pedro C. Barata, Marcelo Lamenza, Sarah Devonshire, Kim Schach, Brian I. Rini, Jorge A. Garcia, Timothy D. Gilligan, Moshe C. Ornstein & Petros Grivas

  4. Division of Hematology and Medical Oncology, University of Wisconsin, Madison, WI, USA

    Hamid Emamekhoo

  5. Roswell Park Cancer Institute, Buffalo, NY, USA

    Marc S. Ernstoff

  6. University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Christopher J. Hoimes

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  1. Alice Tzeng
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Corresponding authors

Correspondence to Moshe C. Ornstein or Petros Grivas.

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No external funding was used in the preparation of this manuscript.

Conflict of Interest

Alice Tzeng, C. Marcela Diaz-Montero, Patricia A. Rayman, Jin S. Kim, Paul G. Pavicic Jr., James H. Finke, Pedro C. Barata, Marcelo Lamenza, Sarah Devonshire, Kim Schach, Hamid Emamekhoo, Marc S. Ernstoff, Christopher J. Hoimes, Brian I. Rini, Jorge A. Garcia, Timothy D. Gilligan, Moshe C. Ornstein, and Petros Grivas declare that they have no conflicts of interest that might be relevant to the contents of this manuscript, and that there has been no significant financial support for this work that could have influenced its outcome.

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Tzeng, A., Diaz-Montero, C.M., Rayman, P.A. et al. Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma. Targ Oncol 13, 599–609 (2018). https://doi.org/10.1007/s11523-018-0595-9

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  • DOI: https://doi.org/10.1007/s11523-018-0595-9

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