TY - JOUR

T1 - Dissecting tumor microenvironment heterogeneity in syngeneic mouse models

T2 - insights on cancer-associated fibroblast phenotypes shaped by infiltrating T cells

AU - Carretta, Marco

AU - Thorseth, Marie Louise

AU - Schina, Aimilia

AU - Agardy, Dennis Alexander

AU - Johansen, Astrid Zedlitz

AU - Baker, Kevin James

AU - Khan, Shawez

AU - Rømer, Anne Mette Askehøj

AU - Fjæstad, Klaire Yixin

AU - Linder, Hannes

AU - Kuczek, Dorota Ewa

AU - Donia, Marco

AU - Grøntved, Lars

AU - Madsen, Daniel Hargbøl

N1 - Publisher Copyright: Copyright © 2024 Carretta, Thorseth, Schina, Agardy, Johansen, Baker, Khan, Rømer, Fjæstad, Linder, Kuczek, Donia, Grøntved and Madsen.

PY - 2024

Y1 - 2024

N2 - Murine syngeneic tumor models have been used extensively for cancer research for several decades and have been instrumental in driving the discovery and development of cancer immunotherapies. These tumor models are very simplistic cancer models, but recent reports have, however, indicated that the different inoculated cancer cell lines can lead to the formation of unique tumor microenvironments (TMEs). To gain more knowledge from studies based on syngeneic tumor models, it is essential to obtain an in-depth understanding of the cellular and molecular composition of the TME in the different models. Additionally, other parameters that are important for cancer progression, such as collagen content and mechanical tissue stiffness across syngeneic tumor models have not previously been reported. Here, we compare the TME of tumors derived from six common syngeneic tumor models. Using flow cytometry and transcriptomic analyses, we show that strikingly unique TMEs are formed by the different cancer cell lines. The differences are reflected as changes in abundance and phenotype of myeloid, lymphoid, and stromal cells in the tumors. Gene expression analyses support the different cellular composition of the TMEs and indicate that distinct immunosuppressive mechanisms are employed depending on the tumor model. Cancer-associated fibroblasts (CAFs) also acquire very different phenotypes across the tumor models. These differences include differential expression of genes encoding extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and immunosuppressive factors. The gene expression profiles suggest that CAFs can contribute to the formation of an immunosuppressive TME, and flow cytometry analyses show increased PD-L1 expression by CAFs in the immunogenic tumor models, MC38 and CT26. Comparison with CAF subsets identified in other studies shows that CAFs are skewed towards specific subsets depending on the model. In athymic mice lacking tumor-infiltrating cytotoxic T cells, CAFs express lower levels of PD-L1 and lower levels of fibroblast activation markers. Our data underscores that CAFs can be involved in the formation of an immunosuppressive TME.

AB - Murine syngeneic tumor models have been used extensively for cancer research for several decades and have been instrumental in driving the discovery and development of cancer immunotherapies. These tumor models are very simplistic cancer models, but recent reports have, however, indicated that the different inoculated cancer cell lines can lead to the formation of unique tumor microenvironments (TMEs). To gain more knowledge from studies based on syngeneic tumor models, it is essential to obtain an in-depth understanding of the cellular and molecular composition of the TME in the different models. Additionally, other parameters that are important for cancer progression, such as collagen content and mechanical tissue stiffness across syngeneic tumor models have not previously been reported. Here, we compare the TME of tumors derived from six common syngeneic tumor models. Using flow cytometry and transcriptomic analyses, we show that strikingly unique TMEs are formed by the different cancer cell lines. The differences are reflected as changes in abundance and phenotype of myeloid, lymphoid, and stromal cells in the tumors. Gene expression analyses support the different cellular composition of the TMEs and indicate that distinct immunosuppressive mechanisms are employed depending on the tumor model. Cancer-associated fibroblasts (CAFs) also acquire very different phenotypes across the tumor models. These differences include differential expression of genes encoding extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and immunosuppressive factors. The gene expression profiles suggest that CAFs can contribute to the formation of an immunosuppressive TME, and flow cytometry analyses show increased PD-L1 expression by CAFs in the immunogenic tumor models, MC38 and CT26. Comparison with CAF subsets identified in other studies shows that CAFs are skewed towards specific subsets depending on the model. In athymic mice lacking tumor-infiltrating cytotoxic T cells, CAFs express lower levels of PD-L1 and lower levels of fibroblast activation markers. Our data underscores that CAFs can be involved in the formation of an immunosuppressive TME.

KW - cancer-associated fibroblasts

KW - immunosuppressive mechanisms

KW - immunotherapy

KW - PD-L1

KW - stroma

KW - syngeneic mouse cancer models

KW - tissue stiffness

KW - tumor microenvironment

U2 - 10.3389/fimmu.2023.1320614

DO - 10.3389/fimmu.2023.1320614

M3 - Journal article

C2 - 38259467

AN - SCOPUS:85182665758

VL - 14

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 1320614

ER -