783 A Brief History of TiME

Stephen Paget considered the founding father of TiME laid the foundations of this research area by formulating the seed and soil theory postulating that metastasis of a particular type of cancer (“the seed”) often metastasizes to certain sites (“the soil”) based on the similarity of the original and secondary tumor sites. Numerous studies in the 1970’s and 1980’s elaborated on the immune and angiogenic factors involved in this interplay of the tumor and its environment by characterizing the functions of cellular and humoral immune components. These studies established that these immune cells including T cells, B cells, NK cells and macrophages had the capacity to infiltrate solid tumors in humans and in animals (reviewed in Witz, 2009). Other early studies from Judah Folkman’s lab appreciated that tumor proliferation was dependent upon blood supply and that the interactions of tumor and endothelial cells initiated and drove this process. Angiogenic factors were then identified in various types of tumors and the possibility was raised that inhibiting such factors or their interaction with endothelial cells could perhaps be of clinical benefit to cancer patients (reviewed by Folkman J, 1972). Subsequent work by others also highlighted the interactions between the stroma and tumor cells. The stroma consists of the extracellular matrix (ECM), which is composed of proteoglycans, hyaluronic acid, and fibrous proteins such as collagen, fibronectin, and laminin; growth factors, chemokines, cytokines, antibodies, and metabolites; and mesenchymal supporting cells (e.g., fibroblasts and adipocytes), cells of the vascular system, and additional cells of the immune system. As tumors develop, the stroma also evolves. 

It was a seminal paper 30 years ago that really changed the landscape of how we view the role of immune cells in the tumor microenvironment. van der Bruggen and colleagues first reported the existence of a human tumor antigen recognized by T-cells. They were able to clone the melanoma antigen-encoding gene (MAGE), which encodes an antigen recognized by cytotoxic T-cells, providing not only evidence that the immune system was capable of seeking and destroying tumor cells but also provided the first identification of a molecular target, one that is actively used clinically for advanced melanoma. 

Today, the complexity and functional contribution of the tumor microenvironment in cancer progression much like our knowledge of the universe continues to expand at the cellular, organ and systemic level. This complexity is observed within not just the variety of cells involved, but also includes metabolism as a form of communication, aging and obesity as microenvironmental factors at the tissue and systemic levels, and the significance of gut microbiota. It is now appreciated that the composition of the tumor microenvironment plays a significant role not just in disease progression, but also in response to therapy, invasion, and metastasis or conversely, restraint of growth for many tumor types. 

Recent work by Grunwald et. al., 2021 have discovered additional complexity to this vast cancer cosmos, with the identification of ‘‘subTMEs,’’ histologically definable tissue states anchored in fibroblast plasticity, with regional relationships to tumor immunity, subtypes, differentiation, and treatment response. They noted that “reactive’’ subTMEs, functionally coordinated fibroblast communities were immune hot and inhabited by aggressive tumor cell phenotypes yet appeared more chemo-sensitive. The matrix-rich ‘‘deserted’’ subTMEs instead harbored fewer activated fibroblasts and tumor-suppressive features but were markedly chemoprotective and enriched upon chemotherapy. Its clear from this study and others that we are still only just beginning to explore these new dimensions addressing the tumor-stroma-immune interplay in tumor progression, patient-specific stromal heterogeneity and how this is linked to clinical outcomes. 

Want to explore this universe in your tissues? Check out some of our newest panels enabling a detailed interrogation of the tumor microenvironment associated with specific cancer types. 

Categories: Uncategorized Tags: | Comments 782 The Path(ology) Not Taken

The practice of anatomic pathology today rests on a century and a half legacy of histopathology – the changes in cells and tissues in various disease states as seen in a microscope.  Virchow and other giants of the 19th century recognized the importance of these changes, and many of their concepts endure.  Visual interpretation of thinly sliced tissue sections, embedded in candle wax and stained blue and pink with the textile dyes hematoxylin and eosin, remains the “gold standard” for diagnosis of many diseases.

I was fortunate in my first job out of college to work with a pathologist, studying changes in heart tissue following our attempts to reverse abnormal heart rhythms.  I remember with awe the fine, delicate detail revealed in tissue sections, as well as the power of careful observation.  I was struck by the diversity of cells – each with the same DNA, yet each with a distinct position, shape, and role in the muscle and its healing process.  How did each cell know who it was, where it was, how to behave, and when to stop or die?

Well, I did become a pathologist but quickly recognized that pathology was largely correlative, full of conjecture, and (at that time) ultimately unable to address these questions.  My journey to answer these questions led me over two decades to molecular and developmental biology, studying mostly fruit flies and mice.  Why?  We now know that cells adopt different identities using combinations of transcription factors and talk to each other with signaling modules, using a mostly ancient and relatively small “toolkit” of proteins that unite not only all of us as humans, but all of the earth’s creatures, including flies and mice.

Times have changed.  Anatomic pathology is at the tipping point of a revolution fueled by advances in biology, technology, digital and computational pathology, and artificial intelligence. These questions about cells can’t be addressed using current immunohistochemical techniques or bulk tissue sequencing, but are amenable to tissue multiplex analyte detection.  In particular, accurate characterization of each cell in tissue biopsy, especially with respect to the “tumor immune microenvironment” (TIME), is increasingly important to characterize cancer tissues and predict response to new therapies. Our innovative InSituPlex staining technology and services offerings can provide key insights into these and other questions important for research and drug development.  Finally, with Ultivue colleagues we’ve summarized our perspectives and view of the future in a peer-reviewed open access article available at the link below.  We welcome your feedback and look forward to using InSituPlex to help solve your tissue mysteries.

Click here to access the Frontiers review article Categories: Uncategorized Tags: | Comments