The Adaptive Complexity of Cancer

Abstract

Cancer treatment options are expanding to the benefit of significant segments of patients. However, their therapeutic power is not equally realized for all cancer patients due to drug toxicity and disease resistance. Overcoming these therapeutic challenges would require a better understanding of the adaptive survival mechanisms of cancer. In this respect, an integrated view of the disease as a complex adaptive system is proposed as a framework to explain the dynamic coupling between the various drivers underlying tumor growth and cancer resistance to therapy. In light of this system view of cancer, the immune system is in principal the most appropriate and naturally available therapeutic instrument that can thwart the adaptive survival mechanisms of cancer. In this respect, new cancer therapies should aim at restoring immunosurveillance by priming the induction of an effective immune response through a judicious targeting of immunosuppression, inflammation, and the tumor nutritional lifeline extended by the tumor microenvironment.

Figure 1

The reprogramming of metabolism in cancer involves positive feedback loops with metabolic outputs such as amino-acids, lactate, and ATP serving as stimuli of the signaling pathways, which are in turn driving the upstream regulators of metabolic enzymes [–43]. PPP, pentose phosphate pathway; ATP, adenosine triphosphate; AMP, adenosine monophosphate; dNTP, deoxynucleotide; α-KG, α-ketoglutarate.

Figure 2

Metabolic pathways of immunosuppression. TME immunosuppression is induced by the elevated concentrations of immunosuppressive metabolites such as lactate, kynurenine, potassium, and adenosine, released in the TME by cancer cells and other TME resident cells [, –53]. ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate; MDSCs, myeloid derived suppressor cells; CAFs, cancer associated fibroblast; Tregs, regulatory T cells; myeloid derived suppressor cells; AK, adenosine kinase.

Figure 3

Immune response and inflammation. The immune response to cancer growth is mediated by multiple feedback loops involving innate and adaptive immune cells and the resulting tumor promoting inflammation [–64]. TAMs, tumor associate macrophages; TANs, tumor associated neutrophils; MDSCs, myeloid derived suppressor cells; DCs, dendritic cells; NKs, natural killer cells; ILCs, Innate lymphoid cells; CTLs, cytotoxic T lymphocytes; MHC, major histocompatibility complex; ECM, extracellular matrix; MMPs, matrix metalloproteinases, PGs, Prostaglandins; NO, Nitric Oxide; DDR, DNA damage response; Th1, T helper 1; Th2, T helper 2; Th17, T helper 17; Treg, T regulatory.

Figure 4

Metabolic inhibition of immune response. Cancer reprograming of metabolism leads to the TME depletion in nutrients such as glucose, glutamine, tryptophan, and arginine [, , –68], and the release of immunosuppressive metabolites such as kynurenine, lactate, and prostaglandins [, –53, 69]. ROS, reactive oxygen species; MDSCs, myeloid derived suppressor cells; CAFs, cancer associated fibroblasts; NKs, natural killer cells; CTLs, cytotoxic T lymphocytes.

Figure 5

The complex adaptive dynamics of cancer are driven by the multiplicity of causal effects and feedbacks coupling the genetically evolving tumor, the response of the immune system, and the changing metabolic state of the TME.

Figure 6

Coarse-grain model of interactions between cancer and immune cells and the effects of the molecular state of the TME.