A Good Defense is the Best Offense: Understanding the Tumor Microenvironment

By Jennifer J.D. Morrissette, PhD, Jonathan P. Belman, MD, PhD, and Andrew J. Rech, MD, PhD

The tumor microenvironment (TME) describes the space in which there is interaction between malignant and nonmalignant cells. Differences in TME composition have been linked to differences in therapeutic response and outcome in many tumor types. Delineating the immunobiology in this space may assist pathologists and oncologists in guiding therapy.

The burden of detecting and interpreting these findings falls to pathologists. It is, therefore, imperative that pathologists and laboratory professionals keep up with the ever-evolving research in immuno-oncoIogy (IO) to determine the best treatments for their patients.

ASCP’s IO Work Group has created a comprehensive strategy to guide the development of specialized IO education, including Tumor Biology 101: Detecting Genomic Targets and Mutation Patterns, for pathologists and laboratory professionals. It also supports the implementation and dissemination of best practices in IO testing, treatment options, and communication in multidisciplinary teams to improve quality of care.

Advances in IO therapy have shown exceptional promise in the treatment of cancer. Somatic mutations—genetic alterations acquired by a cell that can be passed to descendant cells during cell division—are thought to activate a tumor-specific response by T cells. Tumor-infiltrating T lymphocytes (TILs) are a hallmark of this immunosurveillance that occurs in the TME. A high presence of TILs is associated with a favorable clinical outcome in many tumor types.

Scoring TILs by immunohistochemistry (IHC) is complex, but is increasingly considered clinically useful. The type of immune cells, proximity to the tumor margin and density of immune cells can be predictive of response to therapy. One approach integrating these metrics, called the “Immunoscore,” was published in The Lancet in 2018. In this study, T cells in the tumor and in the invasive margin were quantified by digital pathology and the resulting metric had independent prognostic value for risk of recurrence in stage I-III colon cancer.

One mechanism that tumor cells use to escape the T cell response is by hijacking the immune system, inducing T cell exhaustion, and thus evading the immune response. This adaptive immune resistance mechanism in the TME is mediated in part by the receptor-ligand pair PD-1 - PD-L1. Tumor cells can upregulate the ligand PD-L1 on their cell surface, and when recognized by PD-1 expressed by T-cells, limit T cell function. Therapeutic intervention with monoclonal antibodies that disrupt this interaction has been shown to reinvigorate T cells and result in a durable response in some cancer cases.

One of the most critical roles for pathologists today in IO is in the detection of PD-L1 or PD-1 by immunohistochemistry. The detection and accurate scoring of these proteins within the TME is important for clinical decision making in some tumor types. Pathologists oversee that testing is performed on the appropriate tissue and incorporate the results from immunohistochemistry, molecular studies, imaging and other biomarkers into a comprehensive interpretation that can help guide treatment.  

Genomic sequencing is becoming standard of care for diagnosis and treatment decisions for many tumors. The detection of specific gene mutations, as well as more complex genomic changes such as tumor mutational burden and microsatellite instability, can help guide treatment selection. For example, pembrolizumab, an anti-PD-1 monoclonal antibody, is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a high level of microsatellite instability (MSI). MSI-high tumors generally contain a high level of neoantigens which have the potential to be recognized as “non-self” and eliminated by a stimulated immune system.

Neoantigens can also be targeted directly through vaccination; this approach is currently being investigated by numerous clinical trials. Additional metrics such as genomic and transcriptomic signatures that indicate immune activity are also an active area of research and may have prognostic importance. Pathologists are making the choices for which regions of the tumor to sequence and may determine that multiple regions of the tumor need to be sequenced in order to predict the overall response of the tumor. Pathologists have an opportunity to use the exciting research developments of systems immunology to create the next generation of tests to guide clinical decision making.

Find out about ASCP’s specialized IO education for pathologists and laboratory professionals by clicking here.

Jennifer J.D. Morrissette, PhD, is Scientific Director of Clinical Cancer Cytogenetics, Clinical Director of the Center for Personalized Diagnostics, and Associate Professor of Clinical Pathology and Laboratory Medicine in the Department of Pathology at the University of Pennsylvania. She serves on the ASCP Immuno-oncology Work Group. Andrew J. Rech, MD, PhD, is a clinical pathology resident at the University of Pennsylvania. Jonathan Belman, MD, PhD, Is a Fellow in Transfusion Medicine and Therapeutic Pathology at Penn Medicine at the University of Pennsylvania Health System.