Review Article | Published:

Implications of the tumor immune microenvironment for staging and therapeutics

Modern Pathology volume 31, pages 214234 (2018) | Download Citation


Characterizing the tumor immune microenvironment enables the identification of new prognostic and predictive biomarkers, the development of novel therapeutic targets and strategies, and the possibility to guide first-line treatment algorithms. Although the driving elements within the tumor microenvironment of individual primary organ sites differ, many of the salient features remain the same. The presence of a robust antitumor milieu characterized by an abundance of CD8+ cytotoxic T-cells, Th1 helper cells, and associated cytokines often indicates a degree of tumor containment by the immune system and can even lead to tumor elimination. Some of these features have been combined into an ‘Immunoscore’, which has been shown to complement the prognostic ability of the current TNM staging for early stage colorectal carcinomas. Features of the immune microenvironment are also potential therapeutic targets, and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis are especially promising. FDA-approved indications for anti-PD-1/PD-L1 are rapidly expanding across numerous tumor types and, in certain cases, are accompanied by companion or complimentary PD-L1 immunohistochemical diagnostics. Pathologists have direct visual access to tumor tissue and in-depth knowledge of the histological variations between and within tumor types and thus are poised to drive forward our understanding of the tumor microenvironment. This review summarizes the key components of the tumor microenvironment, presents an overview of and the challenges with PD-L1 antibodies and assays, and addresses newer candidate biomarkers, such as CD8+ cell density and mutational load. Characteristics of the local immune contexture and current pathology-related practices for specific tumor types are also addressed. In the future, characterization of the host antitumor immune response using multiplexed and multimodality biomarkers may help predict which patients will respond to immune-based therapies.

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We thank Jessica Esandrio for administrative assistance. This work was supported by the Melanoma Research Alliance (to JMT); Bristol-Myers Squibb (JMT, RAA); Sidney Kimmel Cancer Center Core Grant P30 CA006973 (to JMT, RAA); the National Cancer Institute NIH Grant R01 CA142779 (to JMT); NIH Grant T32 CA193145 (to TRC); Center for Immuno-Oncology, Dana-Farber Cancer Institute (to SJR); The National Cancer Institute of France (INCa), the Canceropole Ile de France, INSERM, the Cancer research for personalized medicine (CARPEM), Paris Alliance of Cancer Research Institutes (PACRI), the LabEx Immuno-oncology, the Society for Immunotherapy of Cancer (SITC) (to JG). We were also supported by the Bloomberg–Kimmel Institute for Cancer Immunotherapy and a Stand Up To Cancer–Cancer Research Institute Cancer Immunology Translational Cancer Research Grant (SU2C-AACR-DT1012). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.

Author information


  1. Department of Dermatology, The Johns Hopkins University SOM and Bloomberg–Kimmel Institute for Immunotherapy, Baltimore, MD

    • Janis M Taube
    •  & Nicolas A Giraldo
  2. Department of Pathology, The Johns Hopkins University SOM and Bloomberg–Kimmel Institute for Immunotherapy, Baltimore, MD, USA

    • Janis M Taube
    • , Tricia R Cottrell
    • , Nicolas A Giraldo
    • , Alexander S Baras
    • , Robert A Anders
    •  & Ashley Cimino-Mathews
  3. Department of Oncology, The Johns Hopkins University SOM and Bloomberg–Kimmel Institute for Immunotherapy, Baltimore, MD, USA

    • Janis M Taube
    •  & Ashley Cimino-Mathews
  4. INSERM, Laboratory of Integrative Cancer Immunology, Paris, France

    • Jérôme Galon
  5. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    • Jérôme Galon
  6. Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche des Cordeliers, Paris, France

    • Jérôme Galon
  7. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    • Lynette M Sholl
    • , Scott J Rodig
    •  & Sanjay S Patel
  8. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    • David L Rimm


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Competing interests

RAA receives grant funding from Bristol-Meyers Squibb (BMS) and Stand Up 2 Cancer and is an advisory board member for BMS and Merck. AC-M receives grant funding from BMS. JG receives grant funding from Astra-Zeneca, MedImmune, Janssen; is co-founder and chairman of the advisory board of HalioDx; and is a consultant/advisory board member for BMS, Merck, Astra-Zeneca, GSK, AMGEN, IObiotech, Northwest Biotherapeutics, Actelion, Novartis, Incyte, Kite Pharma, Mologen, Compugen, NanoString, and Illumina. DLR receives grant funding from Astra Zeneca, Cepheid, Navigate/Novartis, Gilead Sciences, Pierre Fabre, and Perkin Elmer; is a consultant or advisor to Astra Zeneca, Agendia, Bethyl Labs, Biocept, BMS, Cell Signaling Technology, Merck, OptraScan, Perkin Elmer, and Ultivue; and holds equity in Metamark Genetics and PixelGear. SJR receives grant funding from BMS and is a consultant/advisory board member for BMS and Perkin-Elmer. JMT receives grant funding from BMS and is a consultant/advisory board member for BMS, Merck, and Astra-Zeneca. LMS served as an advisory board member for Genentech and consults for Research to Practice. The other authors (ASB, TRC, NAG, SJP) declare no conflict of interest.

Corresponding author

Correspondence to Ashley Cimino-Mathews.

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