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Cancer Essentials - Immunotherapy

Explore current research on immunotherapy – with infographics on modeling tumor immunology and immunotherapy in mice

Editor’s Note: Cancer Essentials is a bi-monthly collection that provides current content on timely topics at the forefront of cancer research and oncology. Its curated by the editors of Trends in Cancer (Cell Press Reviews) and Elsevier's reference books on cancer.


What is cancer? The dominant thinking since the 1980s has been tumor cell-centric: in essence, that cancer is a disease of damaged genes responsible for creating rogue cells. However, starting in the 2000s, this genetic model has been challenged by the idea that cancer is a failure of host immune controls on such rogue cells. Indeed, immunological thought has re-emerged as a dominant force in cancer research, correcting a divorce from the mainstream that had been sealed in the 1980s by the rise of the genetic model. Today, a consensus has emerged on the central importance of the inflammatory tissue microenvironment and the adaptive immune response in promoting malignant development and progression.

The notion that cancer is a disease of immune insufficiency was enunciated initially by Paul Ehrlich over a century ago. So the idea is not new. But since 2000, there have been major advances in understanding how cancers interact with and overcome the immune system. In particular, mechanistic insights into how cancers suppress and evade local and systemic immunity have enabled the development of new immunotherapeutic agents, especially immune checkpoint antibodies, which are now revolutionizing cancer therapy. Building on a textbook edited by Elizabeth Jaffee and myself that has surveyed this area, Cancer Immunotherapy: Immune Suppression and Tumor Growth (Academic Press, Elsevier), the present issue of Cancer Essentials assembles a set of major reviews on cancer immunotherapy. As such, it provides a critical update to a field now recognized as a critical prime mover in effective future combination treatments to eradicate deadly cancers.

About our guest contributor

George C. Prendergast, PhDDr. George Prendergast is an international leader in cancer research, with special expertise in the preclinical discovery and development of molecular therapeutics. As a scientist and inventor, he has over 200 publications and 40 US and international patents and has co-founded or served as director at several startup companies. Since 2010, Dr. Prendergast has been Editor-in-Chief of Cancer Research, the field’s most highly cited journal. His textbook, Cancer Immunology: Immune Suppression and Tumor Growth, now in its second edition, captures the exploding knowledge in ways to shape immunity and restore natural defenses against cancer.

Dr. Prendergast began his career on the faculty of The Wistar Institute (1993-2001) in Philadelphia and was later senior director of an oncology discovery group at the DuPont Pharmaceuticals Company (1999-2001). In 2002, he moved his groups at Wistar and DuPont to the Lankenau Institute for Medical Research (LIMR) to create a unique ‘acapreneurial’ organization that integrates biotech start-up companies with non-profit laboratory and clinical groups to speed translation of discoveries to clinic. From this platform, Dr. Prendergast and his colleagues pioneered the preclinical discovery, validation and clinical translation of indoximod and the first true enzymatic small molecule inhibitors of IDO1, including the bioactive phenylimidazole structural

Modeling tumor immunology and immunotherapy in mice

Sources: Aitziber Buquéand & Lorenzo Galluzzi

Figure 1: Main applications of mouse models for tumor immunology and immunotherapy (Sources: Aitziber Buqué and Lorenzo Galluzzi)

Immunodeficient mice xenografted with human cancer cell lines have been at the foundation of in vivo cancer research for several decades, providing ground for the regulatory approval of multiple chemotherapeutics and targeted anticancer agents, but are intrinsically unsuitable for studying tumor immunology and immunotherapy.

Similarly, patient-derived xenografts (PDXs) established in immunodeficient mice are not subjected to immunosurveillance by the host, although (depending on the protocol employed for PDX generation) some components of the patient’s immune system may be also transferred to the mouse and be active, at least for some time. Considerable efforts are being devoted to the generation of humanized mice to circumvent these limitations.

The establishment of PDXs in immunodeficient mice that alongside are engrafted with matched patient-derived peripheral blood mononuclear cells (PBMCs) is also being investigated as a means to screen for the efficacy of (immuno)therapeutic agents in support of clinical decision making. Mouse cancer cell lines grafted subcutaneously or orthotopically in immunocompetent syngeneic hosts have been instrumental for the development of a variety of immunotherapeutics as well as for the discovery that conventional anticancer regimens including some forms of chemotherapy and radiation therapy can trigger tumor-targeting immune responses.

Carcinogen-driven tumors established in immunocompetent versus immunodeficient animals were critical in the early days of modern tumor immunology as they enabled the discovery of natural anticancer immunosurveillance. Moreover, they allow for investigating the immunological versus non-immunological efficacy of anticancer (immuno)therapeutics in the context of natural immunoediting, clinically-relevant immunobiological heterogeneity and high mutation load. Transgene-driven tumors have generated in-depth insights into the crosstalk between oncogenic drivers and the tumor microenvironment, in both its immunological and non-immunological components. Each of these models is associated with specific advantages and disadvantages (see “Key facts” below).

Figure 2. Key features of mouse models for tumor immunology and immunotherapy.

Key parameters that should be taken into careful consideration when choosing the most appropriate mouse model for the study of tumor immunology and immunotherapy include not only the immunological competence of the host (which is influenced by strain, sex and age) and its immunological compatibility with malignant cells (which is dictated by strain), but also the mutational load of the latter, their immunological history (previous immunoediting), proliferative potential, propensity for neovascularization and metastatic dissemination, as well as their ability to generate an immunostimulatory versus immunosuppressive microenvironment.

Inoculation site is also an important parameter to keep under consideration (not shown). The precise objective of each study dictates which specific combination of such features should be preferred.

Key facts

  • Human cancer cell lines recapitulate several aspects of human cancer biology, but are intrinsically unsuitable for studying tumor immunology and immunotherapy in vivo as they are immunologically incompatible with the host (and hence can only be xenografted into severely immunodeficient mice).
  • Patient-derived xenografts (PDXs) established in immunodeficient mice are advantageous in that they enable personalized tests on the sensitivity of the tumor to conventional therapeutic regimens in vivo, but are also immunologically incompatible with the host
  • When PDXs are established from undigested tissue, the immune infiltrate of the original tumor remains (at least temporarily), and may contribute (at least to some extent) to sensitivity/resistance to treatment
  • A multitude of approaches is being investigated for the development of mouse strains endowed with as many components of the human immune system as possible, potentially enabling in vivo tumor immunology and immunotherapy research on human cancer cells.
  • PDXs established in immunodeficient mice that are also engrafted with matched patient-derived PBMCs offer a privileged platform to test the sensitivity of the tumor to (immuno)therapy in the context of some immunological compatibility, but this model is currently limited by graft-versus-host disease.
  • Multiple barriers still need to be overcome to obtain humanized mice recapitulating several key aspects of the human immune response against cancer
  • Mouse cancer cell lines grafted in immunocompetent syngeneic mice enable the study of several features of anticancer immune responses driven by (immuno)therapy, including the establishment of immunological memory upon rejection.
  • Mouse cancer cell lines have undergone immunoediting in their original host, implying that they do not recapitulate well the natural course of the disease upon implantation, at least from an immunological perspective, even when inoculated orthotopically (rather than subcutaneously) in immunocompetent hosts.
  • Human and mouse cancer cell lines are generated from late-stage lesions, often corresponding to a high proliferative potential, considerable propensity to disseminate locally and/or systemically, and remarkable ability to evade immunosurveillance.
  • Orthotopic grafts models are generally superior to their subcutaneous counterparts as they recapitulate better the natural microenvironment of the tumor, but can be technically challenging to establish and are not always compatible with localized forms of treatment (including surgery and intratumoral drug delivery).
  • Carcinogen-driven tumors established in immunocompetent mice are suitable to study oncogenesis, disease progression and response to therapy in the context of an immunologically intact host (unless the carcinogen is immunosuppressive per se).
  • Carcinogen-driven tumors are generally characterized by a high mutational load, which does not necessarily recapitulate the mutational signature of their human counterparts, and can exhibit considerable degrees of biological and immunological heterogeneity
  • Transgene-driven tumors are advantageous in that they are relatively homogenous and can be  harnessed to study the impact of a single molecular alterations on the (immuno)biology of the disease, including sensitivity to (immuno)therapy
  • Transgene-driven tumors often bear very low amounts of non-synonymous mutations, which renders them poorly sensitive to natural and therapy-driven immunosurveillance
  • Endogenous tumors (both carcinogen- and transgene-driven) established in immunocompetent hosts recapitulate early oncogenesis and disease progression better than transplanted tumors, as they emerge and evolve in the context of a bidirectional crosstalk with the host immune system

Cancer Essentials: Immunotherapy

Cancer and the Immune System

Immune Cells

Immunotherapy and Cancer Therapeutics

Immunotherapy: Clinical Translation

New Pathways and Targets

Tools to Develop Immunotherapies

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