Review Article | Published:

Immunological hallmarks of stromal cells in the tumour microenvironment

Nature Reviews Immunology volume 15, pages 669682 (2015) | Download Citation

Abstract

A dynamic and mutualistic interaction between tumour cells and the surrounding stroma promotes the initiation, progression, metastasis and chemoresistance of solid tumours. Far less understood is the relationship between the stroma and tumour-infiltrating leukocytes; however, emerging evidence suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy. Thus, there is growing interest in elucidating the immunomodulatory roles of the stroma that evolve within the tumour microenvironment. In this Review, we discuss the evidence that stromal determinants interact with leukocytes and influence antitumour immunity, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.

Key points

  • Non-haematopoietic stromal cells in the tumour microenvironment actively interact with infiltrating leukocytes. Emerging evidence also suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy.

  • Dysfunctional endothelial cells and aberrant pericyte coverage in tumour blood vessels results in tortuous and leaky vessels, which greatly impinge on leukocyte infiltration. Diapedesis of effector immune cells is further limited by the reduced expression of endothelial adhesive molecules.

  • Fibroblasts contribute to shaping the immune cell populations in tumours by secreting chemokines that can selectively repel effector T cells while favouring the recruitment of immunosuppressive cells.

  • Stromal cells in the tumour microenvironment can also actively hinder antitumour immunity by several mechanisms, including expression of inhibitory receptors, production of molecules that induce T cell apoptosis and secretion of immunosuppressive factors.

  • Overcoming immune suppression is of the upmost importance for cancer treatment. In light of the increasing evidence that suggests a role for the tumour stroma in limiting antitumour immune responses, we anticipate that therapies targeting stromal cells in the tumour microenvironment will be likely to provide enormous benefits.

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Acknowledgements

The authors would like to thank their colleagues for critical discussions about stromal cells in the TME. The authors have made every effort to cover key points and cite important papers, and they regret not having the space to cite all relevant studies.

Author information

Author notes

    • Viviana Cremasco
    •  & Jillian L. Astarita

    These authors contributed equally to this work.

Affiliations

  1. Department of Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.

    • Shannon J. Turley
    •  & Jillian L. Astarita
  2. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.

    • Viviana Cremasco
  3. Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

    • Viviana Cremasco

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  1. Search for Shannon J. Turley in:

  2. Search for Viviana Cremasco in:

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Competing interests

S.J.T. and J.L.A. are employees of Genentech. V.C. is an employee at Novartis.

Corresponding author

Correspondence to Shannon J. Turley.

Glossary

Extracellular matrix

(ECM). A dense network of various molecules that are secreted by cells into the extracellular space. This matrix provides physical support and structure for the cells and organs in addition to serving as a reserve for important signalling molecules such as chemokines.

Pericytes

Contractile cells of mesenchymal origin that are tightly wrapped around the endothelial cells to form blood vessels.

Cancer-immunity cycle

The multi-step process by which T cells are activated in tumour-draining lymph nodes, traffic into tumours and kill tumour cells. There are many points along this cycle that are inhibited by immunosuppressive cells and molecules.

Peripheral tolerance

The control of self-reactive T cells in the periphery.

Extravasation

The process by which an immune cell exits capillaries to enter peripheral tissues.

RIP1–TAG5 mouse model

A mouse model of pancreatic cancer in which the expression of SV40 large T antigen (TAG) is expressed under the control of the rat insulin promoter 1 (RIP1). This results in the inhibition of tumour suppressor genes, which leads to the formation of tumours as the mice age.

Diapedesis

A more specific term for extravasation referring to leukocytes exiting intact blood vessels. Ligands expressed on the surface of blood endothelial cells interact with receptors on immune cells, allowing them to adhere to the vessels and squeeze through.

M2 macrophages

A subset of macrophages that are involved in wound healing and type 2 immune responses, such as allergic immune responses. They are known to generally contribute to a tumour-supporting and immunosuppressive environment in tumours.

Desmoplasia

The growth of dense connective tissue that often occurs as tumours progress from neoplasms. They are marked by high levels of fibroblasts and fibrotic tissue.

Sonic hedgehog

A signalling molecule that is highly upregulated in several solid tumours. Upon its secretion by tumour cells, it can act on cancer-associated fibroblasts and other surrounding cells to promote desmoplasia.

Indoleamine 2,3-dioxygenase

(IDO). An enzyme implicated in the catabolism of tryptophan, and its expression by myeloid cells correlates with immunosuppression by tryptophan deprivation and exposure to the tryptophan catabolite kynurenine.

Cross-presentation

A process by which antigens taken up through endocytosis enter the cytosol and into the MHC class I presentation pathway. This allows for the presentation of extracellular antigens, such as tumour antigens, to CD8+ T cells.

Peripheral tissue antigens

Certain antigens for which expression is generally restricted to a specific tissue, such as the kidney or lung, in an adult animal. These antigens are also expressed by stromal cells in the thymus and peripheral lymph nodes to allow for negative selection of self-reactive T cells.

Mechanotransduction

A process by which cells convert mechanical stimuli into biological signalling processes. This process allows cells to sense changes in the stiffness of the surrounding tissue and respond accordingly by activating various signalling cascades.

Myofibroblasts

A specialized type of fibroblast that has high levels of α-smooth muscle actin and the ability to strongly contract extracellular matrix in its surrounding tissue.

Sentinel lymph nodes

The first set of lymph nodes that drains a tumour. These lymph nodes can potentially contain a high concentration of tumour antigens and inflammatory molecules secreted by the tumour.

Hepatic stellate cells

A population of pericytes present in the liver in close association with the sinusoidal endothelial cells.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous set of cells of myeloid origin that can suppress T cell activity.

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DOI

https://doi.org/10.1038/nri3902

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