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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 9/2019

01-09-2019 | Colorectal Cancer | Translational Research and Biomarkers

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

Authors: Jenny Lazarus, MD, Morgan D. Oneka, BS, Souptik Barua, MS, Tomasz Maj, PhD, Mirna Perusina Lanfranca, PhD, Lawrence Delrosario, MD, Lei Sun, PhD, J. Joshua Smith, MD, PhD, Michael I. D’Angelica, MD, Jinru Shia, MD, Jiayun M. Fang, MD, Jiaqi Shi, MD, PhD, Marina Pasca Di Magliano, PhD, Weiping Zou, MD, PhD, Arvind Rao, PhD, Timothy L. Frankel, MD

Published in: Annals of Surgical Oncology | Issue 9/2019

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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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Metadata
Title
Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells
Authors
Jenny Lazarus, MD
Morgan D. Oneka, BS
Souptik Barua, MS
Tomasz Maj, PhD
Mirna Perusina Lanfranca, PhD
Lawrence Delrosario, MD
Lei Sun, PhD
J. Joshua Smith, MD, PhD
Michael I. D’Angelica, MD
Jinru Shia, MD
Jiayun M. Fang, MD
Jiaqi Shi, MD, PhD
Marina Pasca Di Magliano, PhD
Weiping Zou, MD, PhD
Arvind Rao, PhD
Timothy L. Frankel, MD
Publication date
01-09-2019
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 9/2019
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-019-07508-3

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