Immunological thought in the mainstream of cancer research: Past divorce, recent remarriage and elective affinities of the future

Abstract

Immunological thought is exerting a growing effect in cancer research, correcting a divorce that occurred in the mainstream of the field decades ago just as cancer genetics began to emerge as a dominant movement. Today, with a general consensus on the significance of epigenetics, the inflammatory cancer microenvironment and the immune response in determining cancer pathophysiology, a new synthesis of thought is being spurred by a remarriage with cancer immunology, with great implications for the future of the field. This perspective offers a view on how this synthesis is impacting both the understanding and treatment of cancer using adjuvant immunomodulatory modalities in the context of surgical, radiotherapeutic and chemotherapeutic interventions which are present standards of care. With the revolutions in immunochemotherapy and immunoradiotherapy coming this decade, the next great challenge faced by the field will be how to identify simple, cost effective and broadly applicable solutions that do not rely deeply on personalized characters, in an effort to minimize the daunting complexity and costs of a problem that challenges not only physicians and patients but also health care systems and insurers caring for aging populations in the developed world.

Figure 1. Perspective on the historical impact of immunological thought in cancer research. A key event in changing the impact of immunological thought on cancer research may have been the generation of nude mice as an immunocompromised animal system for tumor formation and treatment studies. In permitting human tumor xenograft models to be developed, the nude mouse had a huge influence on the identification of cytotoxic chemotherapeutic drugs for solid tumors. Nude mice have similar rates of spontaneous cancer, which was interpreted as a sign that the immune system was unimportant to cancer formation or control, but the presence of natural killer (NK) cells that exert powerful anticancer effects in nude mice was not appreciated until much later. Later studies in transgenic models corrected this view, but the ‘divorce’ that had occurred to weaken the mainstream perspective on cancer immunology was not healed for decades, as genetics and cell biology became major drivers in what became a mainly ‘cancer cell centric’ field until the 2000s.

Figure 2. Synthetic model of immunoediting and oncogenesis. Oncogenesis creates neoantigens recognized by the immune system, but it also creates plasticity that drives a continuous battle between cancer cells and the immune system on the basis of evolving neoantigen recognition. Analogous to the manner in which bacteria can evolve resistance to antibiotics, but with the advantages of plasticity conferred by oncogenesis, cancer cells evolve tactics for immune resistance. The iteration of escape mechanisms evolved by cancer cells can lead to progressive states of equilibrium and escape, representing clinical dormancy or progressive disease, respectively. To the degree that arising cancer cell mutations may influence local immune modifiers and microenvironment which dominate tumor progression, they may remain forces in driving immune escape and thereby progression to clinical relevance. This model was presented previously in the context of IDO studies.

Figure 3. Immunochemotherapy of the future. The new synthesis of immunological thought with the mainstream of cancer research is stimulating the creation and evaluation of new combinations of therapies that can stimulate the immune system, relieve the immune blockades erected by tumor cells (which have historically hampered immunotherapy), and trigger pro-immunogenic tumor cell deaths. Immune blockades erected by tumors are associated with an altered inflammatory ‘flavor’ of their microenvironment, switching its character from antagonistic to supportive for tumor outgrowth. Conceptually, therapeutics that reprogram the inflammatory ‘flavor’ or block tolerance may prove to be genetically overlapping in action, as suggested by studies of IDO pathway inhibitors.