Single Cell Biology in Cancer Research and Treatment

Gavin Gordon, PhD, Senior Director, Global Pharma & Clinical Trials Alliances, Fluidigm Corporation

Q: What do you see as the best roll for single cell biology in cancer research and treatment in the near future?
A: Supporting immuno-oncology research and development.
Single cell biology refers to the analysis of individual cells isolated from complex tissues obtained from multi-cellular organisms and can be applied to many biologically relevant areas of study. For example, the identification and characterization of various cell compartments, the study of cell fate including lineage mapping and phenotypic plasticity, and understanding mechanisms of tumorigenesis.
Why is it important to conduct single cell studies in the first place? Because biology is heterogeneous. So are complex tissues. And even among relatively homogenous tissues, morphologically speaking, it’s well understood that RNA and protein expression profiles at the whole tissue (or “bulk” level) do not correlate with those of individual cells or cell populations. The same is true for function. A biliary epithelial cell has a different purpose, and gene/protein expression pattern, than a hepatocyte. B cells function differently than T cells in mediating the body’s defense against foreign invaders. Yet both differences would be obscured simply by studying “liver” or “lymphocytes”, respectively.
What is immuno-oncology and why is it so important? Cancer as a disease is also inherently and fundamentally heterogeneous. Cancer cells proliferate and give rise to multiple generations of progeny with distinct genetic mutation profiles. These profiles relate to pathophysiological processes, like metastasis of tumor cells or tumor-induced angiogenesis, for example. This is partly why small molecule therapies that target specific tumor mutations (like BRAF and EGFR inhibitors) modestly extend the life of cancer patients and nearly always result in tumor recurrence; not every cell in the tumor contains the targeted mutation and the resulting “resistant” cells grow to repopulate the tumor post-treatment.
As with the individual cancer cells that comprise a tumor, the immunological microenvironment in which tumors grow is similarly heterogeneous and can benefit from a single cell approach to analysis. Immuno-oncology pertains to the discovery and development of therapies (“immunotherapies”) that target the body’s immune system to help fight cancer. Immunotherapy cancer treatments work in different ways. Some boost the body’s immune system in a very general way. Others help train the immune system to attack cancer cells specifically. In all cases, critical to developing effective immunotherapies is a comprehensive understanding, at a single cell level, of the cellular immune compartment associated with specific tumors.
Recent advances in cancer immunotherapies, and promise of more to come, represent the greatest leap forward for dramatically extending the life of cancer patients since the advent of chemotherapy in the middle of the previous century. While targeted therapies are associated with a modest survival benefit, immunotherapies can be associated with a more durable response in some cases. For example, approximately 25% of advanced melanoma patients receiving an early immunotherapy (the immune checkpoint inhibitor ipilumimab/Yervoy) survive 3 to 10 years post-treatment. In addition, the presence and relative abundance of various immune cell types in the tumor microenvironment may have predictive or prognostic value. These differences can only be teased out with a single cell approach. Many scientists believe that a deepening appreciation of oncology genomics and the quantity and type of antigens expressed by the tumor cells, when coupled with an analysis of the patient’s immune system, will greatly progress the field and unlock the next generation of immunotherapies, many of which no doubt will be combined with targeted therapies and conventional chemotherapy to fight cancer on multiple fronts.
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