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. It's 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
Dr. 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
Sources: Aitziber Buquéand & 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).
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.
- 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
- Cancer as a Systemic Disease That Requires a Systemic Approach, Irina Kareva, Understanding Cancer from a Systems Biology Point of View
- Notable Approaches to Cancer Immunotherapy, Gajanan V. Sherbet, Molecular Approach to Cancer Management
- Immune Response to Cancer Therapy: Mounting an Effective Antitumor Response and Mechanisms of Resistance, Terry R. Medler, Tiziana Cotechini, Lisa M. Coussens, Trends in Cancer
- Cancer Immunoediting: From Surveillance to Escape, Michele W.L. Teng, Michael H. Kershaw, Mark J. Smyth, Cancer Immunotherapy (Second Edition)
- Migrating into the Tumor: a Roadmap for T Cells, Lieke L. van der Woude, Mark A.J. Gorris, Altuna Halilovic, Carl G. Figdor, I. Jolanda M. de Vrie, Trends in Cancer
- γδ T Cells: Unexpected Regulators of Cancer Development and Progression, Christopher Fleming, Samantha Morrissey, Yihua Cai, Jun Yan, Trends in Cancer
- Metabolic Regulation of Tregs in Cancer: Opportunities for Immunotherapy, Haiping Wang, Fabien Franco, Ping-Chih H, Trends in Cancer
- B Lymphocytes and Cancer: A Love–Hate Relationship, Grace J. Yuen, Ezana Demissie, Shiv Pilla, Trends in Cancer
- JAK/STAT Signaling in Myeloid Cells: Targets for Cancer Immunotherapy, Saul J. Priceman, Jiehui Deng, Richard Jove, Hua Yu, Cancer Immunotherapy (Second Edition)
Immunotherapy and Cancer Therapeutics
- Immunotherapy and Cancer Therapeutics: A Rich Partnership, Gang Chen, Elizabeth M. Jaffee, Leisha A. Emens, Cancer Immunotherapy (Second Edition)
- Targeted Therapy and Immunosuppression in the Tumor Microenvironment, Michael J. Allegrezza, Jose R. Conejo-Garcia, Trends in Cancer
- Radiotherapy: Changing the Game in Immunotherapy, Sandra Demaria, C. Norman Coleman, Silvia C. Formenti, Trends in Cancer
- Immune Priming of the Tumor Microenvironment by Radiation, Wen Jiang, Charles K. Chan, Irving L. Weissman, Betty Y.S. Kim, Stephen M. Hahn, Trends in Cancer
Immunotherapy: Clinical Translation
- Reprogramming Tumor Blood Vessels for Enhancing Immunotherapy, Martina Schmittnaegel, Michele De Palma, Trends in Cancer
- HyperAcute Vaccines: A Novel Cancer Immunotherapy, Gabriela R. Rossi, Nicholas N. Vahanian, W. Jay Ramsey, Charles J. Link, Cancer Immunotherapy (Second Edition)
- Re-Emergence of Dendritic Cell Vaccines for Cancer Treatment, Mansi Saxena, Nina Bhardwaj, Trends in Cancer
- Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’, George C. Prendergast, Arpita Mondal, Souvik Dey, Lisa D. Laury-Kleintop, Alexander J. Muller, Trends in Cancer
- Monoclonal Antibodies for Cancer Therapy and Prevention: Paradigm Studies in Targeting the neu/ERBB2/HER2 Oncoprotein, Hongtao Zhang, Arabinda Samanta, Yasuhiro Nagai, Hiromichi Tsuchiya, Takuya Ohtani, Zheng Cai, Zhiqiang Zhu, Jing Liu, Mark I. Greene, Cancer Immunotherapy (Second Edition)
- Immunotherapy and Prevention of Pancreatic Cancer, Alexander H. Morrison, Katelyn T. Byrne, Robert H. Vonderheide, Trends in Cancer
New Pathways and Targets
- The Unfolded Protein Response in Immunogenic Cell Death and Cancer Immunotherapy, Nicole Rufo, Abhishek D. Garg, Patrizia Agostinis, Trends in Cancer
- Learning from the Proteasome How To Fine-Tune Cancer Immunotherapy, Nathalie Vigneron, Joanna Abi Habib, Benoit J. Van den Eynde, Trends in Cancer
- Arginase, Nitric Oxide Synthase, and Novel Inhibitors of L-arginine Metabolism in Immune Modulation, Mariecristina Chioda, Susanna Mandruzzato, Simone Mocellin, Vincenzo Bronte, Cancer Immunotherapy (Second Edition)
- Anti-CD73 in Cancer Immunotherapy: Awakening New Opportunities, Luca Antonioli, Gennady G. Yegutkin, Pál Pacher, Corrado Blandizzi, György Haskó, Trends in Cancer
Tools to Develop Immunotherapies
- Improving Cancer Immunotherapies through Empirical Neoantigen Selection, Catarina Nogueira, Johanna K. Kaufmann, Hubert Lam, Jessica B. Flechtner, Trends in Cancer
- Molecular Profiling of Immunotherapeutic Resistance, Davide Bedognetti, Ena Wang, Marimo Sato-Matsushita, Francesco M. Marincola, Maria Libera Ascierto, Cancer Immunotherapy (Second Edition)
- Microfluidics: A New Tool for Modeling Cancer–Immune Interactions, Alexandra Boussommier-Calleja, Ran Li, Michelle B. Chen, Siew Cheng Wong, Roger D. Kamm, Trends in Cancer
- Cancer Nanomedicine: Lessons for Immuno-Oncology, Shiladitya Sengupta, Trends in Cancer