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Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells

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

Abstract

Background

Although immune-based therapy has proven efficacious for some patients with microsatellite instability (MSI) colon cancers, a majority of patients receive limited benefit. Conversely, select patients with microsatellite stable (MSS) tumors respond to checkpoint blockade, necessitating novel ways to study the immune tumor microenvironment (TME). We used phenotypic and spatial data from infiltrating immune and tumor cells to model cellular mixing to predict disease specific outcomes in patients with colorectal liver metastases.

Methods

Formalin fixed paraffin embedded metastatic colon cancer tissue from 195 patients were subjected to multiplex immunohistochemistry (mfIHC). After phenotyping, the G-function was calculated for each patient and cell type. Data was correlated with clinical outcomes and survival.

Results

High tumor cell to cytotoxic T lymphocyte (TC-CTL) mixing was associated with both a pro-inflammatory and immunosuppressive TME characterized by increased CTL infiltration and PD-L1+ expression, respectively. Presence and engagement of antigen presenting cells (APC) and helper T cells (Th) were associated with greater TC-CTL mixing and improved 5-year disease specific survival compared to patients with a low degree of mixing (42% vs. 16%, p = 0.0275). Comparison of measured mixing to a calculated theoretical random mixing revealed that PD-L1 expression on APCs resulted in an environment where CTLs were non-randomly less associated with TCs, highlighting their biologic significance.

Conclusion

Evaluation of immune interactions within the TME of metastatic colon cancer using mfIHC in combination with mathematical modeling characterized cellular mixing of TCs and CTLs, providing a novel strategy to better predict clinical outcomes while identifying potential candidates for immune based therapies.

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Acknowledgment

This work was supported by NIH K08CA201581(tlf) and K08CA234222 (js). M.O. was supported by T32 GM070449. A.R. and S.B were supported by CPRIT RP170719, CPRIT RP150578, NCI 1R37CA214955-01A1, a gift from Agilent Technologies, and a Research Scholar Grant from the American Cancer Society (RSG-16-005-1).

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Authors and Affiliations

  1. Department of Surgery, University of Michigan, Ann Arbor, MI, USA

    Jenny Lazarus MD, Tomasz Maj PhD, Mirna Perusina Lanfranca PhD, Lawrence Delrosario MD, Lei Sun PhD, Marina Pasca Di Magliano PhD, Weiping Zou MD, PhD & Timothy L. Frankel MD

  2. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    J. Joshua Smith MD, PhD & Michael I. D’Angelica MD

  3. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jinru Shia MD

  4. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Jiayun M. Fang MD & Jiaqi Shi MD, PhD

  5. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA

    Arvind Rao PhD

  6. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    Morgan D. Oneka BS, Souptik Barua MS & Arvind Rao PhD

  7. Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA

    Arvind Rao PhD

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  1. Jenny Lazarus MD
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  16. Timothy L. Frankel MD
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Corresponding author

Correspondence to Timothy L. Frankel MD.

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Disclosures

A Rao is a member of Voxel Analytics, LLC, reports receiving other commercial research support from Agilent Technologies. J. Smith has received travel support for fellow education from Intuitive Surgical Inc. and has served as a clinical advisor for Guardant Health, Inc. All other authors have no relevant financial disclosures.

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Lazarus, J., Oneka, M.D., Barua, S. et al. Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells. Ann Surg Oncol 26, 2821–2830 (2019). https://doi.org/10.1245/s10434-019-07508-3

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  • DOI: https://doi.org/10.1245/s10434-019-07508-3

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