Trends in Cancer
Volume 6, Issue 7, July 2020, Pages 605-618
Journal home page for Trends in Cancer

Review
Turning Cold into Hot: Firing up the Tumor Microenvironment

https://doi.org/10.1016/j.trecan.2020.02.022Get rights and content

Highlights

  • Understanding the composition, proportion, activation, or functional states of immune infiltrates within the TME are critical for both diagnosis and therapeutic intervention.

  • There remains the need to develop novel technologies to explore the primary and metastatic TME ex vivo or in situ.

  • ‘Hot’ tumors are characterized by the accumulation of proinflammatory cytokines and T cell infiltration, and have a better response rate to ICB treatment.

  • Alterations of endogenous innate immunity sensing within tumor cells could transduce the signals of cell transformation and malignancy to the TME and consequently regulate antitumor immunity.

  • Dysregulated cellular signaling and metabolism within tumor cells would affect the TME and response to immunotherapy.

Cancers develop within complex tissue environments consisting of diverse innate and adaptive immune cells, along with stromal cells, vascular networks, and many other cellular and noncellular components. The high heterogeneity within the tumor microenvironment (TME) remains a key obstacle in understanding and treating cancer. Understanding the dynamic functional interplay within this intricate ecosystem will provide important insights into the design of effective combinatorial strategies against cancer. Here, we present recent technical advances to explore the complexity of the TME. Then, we discuss how innate immune sensing machinery, genetic alterations of oncogenic signaling, cellular metabolism, and epigenetic factors are involved in modulating the TME. Finally, we summarize the potential strategies to boost antitumor immunity by therapeutically exploiting the TME.

Section snippets

Exploring the TME

For many decades, efforts have been made to identify the genetic driver mutations of cancer initiation and progression. However, cancer progression is not solely determined by genetic alterations within tumor cells but is also critically regulated by the surrounding niche, which may provide important factors promoting cancer development or escape from the surveillance of the host immune system [1]. Since Rudolf Virchow observed leukocytes in neoplastic tissues and first proposed the link

Understanding the Complexity and Heterogeneity of the TME: ‘Cold’ versus ‘Hot’

The density and diversity of tumor-infiltrating immune cells are closely related to prognosis and prediction of treatment efficacy. Thus, understanding the differential composition of immune cells between the primary and metastatic TME may represent an important factor that greatly affects the response to distinct immunotherapy strategies [8,9]. Moreover, different patients with the same cancer type may differ greatly in immune cell composition within the TME, indicating that mapping the

Therapeutically Exploiting the TME to Boost Antitumor Immunity

Tumor cells develop various strategies to evade immune surveillance and the aforementioned highly immunosuppressive/metabolically stressed TME remain major barriers hindering effective antitumor immunity. In this section, we discuss several key steps of TME modulation with a particular focus on innate immune-sensing machinery, genetic alterations of oncogenic signaling, cellular metabolism, and epigenetic regulators. In addition, we present potential strategies to target those regulators within

Concluding Remarks

We now recognize that the TME is a highly dynamic network during tumor progression or upon therapeutic interventions. Thus, developing novel high throughput single-cell approaches, which could combine multiomics profiling in a spatial context within the TME, will enable in depth characterization of phenotypic, functional features of diverse cell types and better reveal their crosstalk at various stages of cancer development and metastasis (see Outstanding Questions). Nevertheless, it remains

Acknowledgments

The authors would like to thank Dr Isabel C. Lopez-Mejia for critical reading of the manuscript. L.Z. is supported by Natural Science Foundation of China (NSFC 81971466) and Innovation Fund from the Chinese Academy of Medical Sciences (2016-I2M-1-005). J. Zheng. is supported by National Key R&D Program of China (2018YFA0900900) and Jiangsu Provincial Key Medical Discipline, the Project of Invigorating Health Care through Science, Technology and Education (No. ZDXKA2016014).

Glossary

Epigenetics
certain chromatin modifications that can modulate gene expression without altering DNA coding sequence.
Immune surveillance
surveillance from both innate and adaptive immunity to recognize and monitor tumor growth.
Immunogenicity
the ability of a foreign substance to confer a certain level of immunity to the host.
Metastasis
spreading of primary tumor in adjacent or distant organ/tissue.
Tumor microenvironment
an intricate ecosystem that is highly heterogenous and dynamic, which consists of

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