The Biology of Immune-Active Cancers and Their Regulatory Mechanisms

  • Davide Bedognetti
  • Alessandra Cesano
  • Francesco M. Marincola
  • Ena WangEmail author
Part of the Cancer Treatment and Research book series (CTAR, volume 180)


The development of cancer results from the evolutionary balance between the proliferating aptitude of cancer cells and the response of the host’s tissues. Some cancers are characterized by genetic instability dependent upon impaired DNA repair mechanisms that lead to the chaotic disruption of multiple cellular functions often in excess of the cancer survival needs and may exert broad effects on surrounding tissues, some beneficial and some detrimental to cancer growth. Among them, inflammatory processes that accompany wound healing may initiate a reaction of the host against the neo-formation. This is possibly triggered by the release by dying cancer cells of molecules known as Damage-Associated Molecular Patterns (DAMPs) following a process termed Immunogenic Cell Death (ICD) that initiates an immune response through innate and adaptive mechanisms. Indeed, analysis of large cancer data sets has shown that ICD is strictly associated with the activation of other immune effector or immune-regulatory pathways. Here, we will describe how immune activation and compensatory immune-regulatory mechanisms balance anti-cancer immune surveillance and the roles that innate and adaptive immunity play including the weight that neo-epitopes may exert as initiators and sculptors of high-affinity memory and effector immune responses against cancer. We will discuss the evolutionary basis for the existence of immune checkpoints and how several theories raised to explain cancer resistance to immunotherapy represent a facet of a similar evolutionary phenomenon that we described in the Theory of Everything. We will show how the biology of immunogenicity and counterbalancing immune regulation is widespread across cancers independent of their ontogenesis while subtle idiosyncratic differences are discernible among them. Finally, we will suggest that overcoming immune resistance implies distinct approaches relevant to the immune context of individual cancers.



Adoptive Cell Therapy


Cancer Immune Responsiveness


Checkpoint Inhibitor Therapy


Damage-Associated Molecular Patterns


Digital Spatial Profiling


High Mobility Group Box 1


Immunogenic Cell Death


Immunologic Constant of Rejection


Indoleamine 2,3-Dioxygenase






Immune Oncology


Nitric Oxide Synthase


Programmed Cell Death Protein Ligand 1


The Cancer Genome Atlas


Transforming Growth Factor


Tumor-Infiltrating Lymphocytes


T cell Immunoglobulin and Mucin-domain containing-3/Hepatitis A Virus Cellular Receptor 2


Tumor Inflammation Signature


Tumor Mutational Burden


Tumor Micro-environment


Two Option Choice


Theory Of Everything


Vascular Endothelial Growth Factor


V-domain Immunoglobulin Suppressor of T cell Activation


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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Davide Bedognetti
    • 1
  • Alessandra Cesano
    • 2
  • Francesco M. Marincola
    • 3
  • Ena Wang
    • 4
    Email author
  1. 1.Sidra ResearchDohaQatar
  2. 2.Essa PharmaSouth San FranciscoUSA
  3. 3.Refuge BiotechnologiesMenlo ParkUSA
  4. 4.AllogeneSouth San FranciscoUSA

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