Cancer Immunology Research Research Articles

The Evolution of Mouse Models of Cancer: Past, Present, and Future.

In the nearly 50 years since the original models of cancer first hit the stage, mouse models have become a major contributor to virtually all aspects of cancer research, and these have evolved well beyond simple transgenic or xenograft models to encompass a wide range of more complex models. As the sophistication of mouse models has increased, an explosion of new technologies has expanded the potential to both further develop and apply these models to address major challenges in cancer research. In the current era, cancer modeling has expanded to include nongermline genetically engineered mouse models (GEMMs), patient-derived models, organoids, and adaptations of the models better suited for cancer immunology research. New technologies that have transformed the field include the application of CRISPR-Cas9-mediated genome editing, in vivo imaging, and single-cell analysis to cancer modeling. Here, we provide a historical perspective on the evolution of mouse models of cancer, focusing on how far we have come in a relatively short time and how new technologies will shape the future development of mouse models of cancer.

Tumor cell membrane‐based vaccines: A potential boost for cancer immunotherapy

AbstractBecause therapeutic cancer vaccines can, in theory, eliminate tumor cells specifically with relatively low toxicity, they have long been considered for application in repressing cancer progression. Traditional cancer vaccines containing a single or a few discrete tumor epitopes have failed in the clinic, possibly due to challenges in epitope selection, target downregulation, cancer cell heterogeneity, tumor microenvironment immunosuppression, or a lack of vaccine immunogenicity. Whole cancer cell or cancer membrane vaccines, which provide a rich source of antigens, are emerging as viable alternatives. Autologous and allogenic cellular cancer vaccines have been evaluated as clinical treatments. Tumor cell membranes (TCMs) are an intriguing antigen source, as they provide membrane‐accessible targets and, at the same time, serve as integrated carriers of vaccine adjuvants and other therapeutic agents. This review provides a summary of the properties and technologies for TCM cancer vaccines. Characteristics, categories, mechanisms, and preparation methods are discussed, as are the demonstrable additional benefits derived from combining TCM vaccines with chemotherapy, sonodynamic therapy, phototherapy, and oncolytic viruses. Further research in chemistry, biomedicine, cancer immunology, and bioinformatics to address current drawbacks could facilitate the clinical adoption of TCM vaccines.

Cancer immunity by tissue-resident type 1 innate lymphoid cells and killer innate-like T cells.

Cancer progression can be restrained by tumor-infiltrating lymphocytes in a process termed cancer immunosurveillance. Based on how lymphocytes are activated and recruited to the tumor tissue, cancer immunity is either pre-wired, in which innate lymphocytes and innate-like T cells are directly recruited to and activated in tumors following their differentiation in primary lymphoid organs; or priming-dependent, in which conventional adaptive T cells are first primed by cognate antigens in secondary lymphoid organs before homing to and reactivated in tumors. While priming-dependent cancer immunity has been a focus of cancer immunology research for decades, in part due to historical preconception of cancer theory and tumor model choice as well as clinical success of conventional adaptive T cell-directed therapeutic programs, recent studies have revealed that pre-wired cancer immunity mediated by tissue-resident type 1 innate lymphoid cells (ILC1s) and killer innate-like T cells (ILTCKs) is an integral component of the cancer immunosurveillance process. Herein we review the distinct ontogenies and cancer-sensing mechanisms of ILC1s and ILTCKs in murine genetic cancer models as well as the conspicuously conserved responses in human malignancies. How ILC1s and ILTCKs may be targeted to broaden the scope of cancer immunotherapy beyond conventional adaptive T cells is also discussed.

Biomarkers and experimental models for cancer immunology investigation.

The rapid advancement of tumor immunotherapies poses challenges for the tools used in cancer immunology research, highlighting the need for highly effective biomarkers and reproducible experimental models. Current immunotherapy biomarkers encompass surface protein markers such as PD-L1, genetic features such as microsatellite instability, tumor-infiltrating lymphocytes, and biomarkers in liquid biopsy such as circulating tumor DNAs. Experimental models, ranging from 3D in vitro cultures (spheroids, submerged models, air-liquid interface models, organ-on-a-chips) to advanced 3D bioprinting techniques, have emerged as valuable platforms for cancer immunology investigations and immunotherapy biomarker research. By preserving native immune components or coculturing with exogenous immune cells, these models replicate the tumor microenvironment in vitro. Animal models like syngeneic models, genetically engineered models, and patient-derived xenografts provide opportunities to study in vivo tumor-immune interactions. Humanized animal models further enable the simulation of the human-specific tumor microenvironment. Here, we provide a comprehensive overview of the advantages, limitations, and prospects of different biomarkers and experimental models, specifically focusing on the role of biomarkers in predicting immunotherapy outcomes and the ability of experimental models to replicate the tumor microenvironment. By integrating cutting-edge biomarkers and experimental models, this review serves as a valuable resource for accessing the forefront of cancer immunology investigation.

The Cancer Moonshot Immuno-Oncology Translational Network at 5: accelerating cancer immunotherapies.

The Immuno-Oncology Translational Network (IOTN) was established in 2018 as part of the Cancer Moonshot. In 2022, President Joe Biden set new goals to reduce the cancer death rate by half within 25 years and improve the lives of people with cancer and cancer survivors. The IOTN is focused on accelerating translation of cancer immunology research, from bench to bedside, and improving immunotherapy outcomes across a wide array of cancers in the adult population. The unique structure and team science approach of the IOTN is designed to accelerate discovery and evaluation of novel immune-based therapeutic and prevention strategies. In this article, we describe IOTN progress to date, including new initiatives and the development of a robust set of resources to advance cancer immunology research. We summarize new insights by IOTN researchers, some of which are ripe for translation for several types of cancers. Looking to the future, we identify barriers to the translation of immuno-oncology concepts into clinical trials and key areas for action and improvements that are suitable for high-yield investments. Based on these experiences, we recommend novel National Institutes of Health funding mechanisms and development of new resources to address these barriers.

Fundamental Characterization of Antibody Fusion-Single-Chain TNF Recombinant Proteins Directed against Costimulatory TNF Receptors Expressed by T-Lymphocytes.

The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference in TNFR costimulation contributes to T cell responses. In this study, to clarify the functional significance of four different TNFRs, OX40, 4-1BB, CD27 and GITR, we prepared corresponding single-chain TNF ligand proteins (scTNFLs) connected to IgG Fc domain with beneficial characteristics, i.e., Fc-scOX40L, Fc-sc4-1BBL, Fc-scCD27L (CD70) and Fc-scGITRL. Without intentional cross-linking, these soluble Fc-scTNFL proteins bound to corresponding TNFRs induced NF-kB signaling and promoted proliferative and cytokine responses in CD4+ and CD8+ T cells with different dose-dependencies in vitro. Mice injected with one of the Fc-scTNFL proteins displayed significantly augmented delayed-type hypersensitivity responses, showing in vivo activity. The results demonstrate that each individual Fc-scTNFL protein provides a critical costimulatory signal and exhibits quantitatively distinct activity toward T cells. Our findings provide important insights into the TNFR costimulation that would be valuable for investigators conducting basic research in cancer immunology and also have implications for T cell-mediated immune regulation by designer TNFL proteins.

Abstract 3165: ImmuneSig: A deep learning framework to develop gene expression signature of immune checkpoint inhibitor therapy

Abstract Immune checkpoint inhibitor (ICI) therapy targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD1), and programmed death-ligand 1 (PDL1) induces durable remission in some patients with various cancer types. Given the variable patient outcomes, many studies have been conducted to identify prognostic biomarkers associated with ICI response. However, due to intra- and inter-tumor heterogeneity and the complexity of the immune system, those biomarkers have diverse efficacy for predicting outcomes in clinical trials. Here we propose a deep learning framework with unsupervised self-learning autoencoders that identifies predictive features from patient transcriptomics data. This approach allows us to determine the contribution of each gene to the response classifier and identifies potential gene signatures for predicting immunotherapy response by using the learned weights of trained autoencoders. We applied our framework to 20+ ICI clinical cohorts across different cancer types and compared the prediction performance of our method with other well-known immune response markers evaluated using a suite of machine learning algorithms (random forest, logistic regression, and XGboosting) with cross-validation. We found that in some cohorts, the learned features from autoencoders improve the predictive power of ICI response when evaluated with the area under the operating characteristic curve. Our framework uncovers potential immune gene signatures associated with patient outcomes. Our work will help advance cancer immunology and immuno-oncology research, provide insights into tumor immunity, and lead to the discovery of progressively more immune markers and novel immune targets. Citation Format: Yang Liu, Aashna Jhaveri, Sudhenshna Bodapati, Cheryl Wong, Franziska Michor. ImmuneSig: A deep learning framework to develop gene expression signature of immune checkpoint inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3165.

Editors' Selections from Relevant Scientific Publications

Highlights from the Literature| April 03 2023 Editors' Selections from Relevant Scientific Publications Author & Article Information Online ISSN: 1940-6215 Print ISSN: 1940-6207 ©2023 American Association for Cancer Research2023American Association for Cancer Research Cancer Prev Res (Phila) (2023) 16 (4): 185. https://doi.org/10.1158/1940-6207.CAPR-16-4-HFL Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record April 3 2023 Citation Editors' Selections from Relevant Scientific Publications. Cancer Prev Res (Phila) 1 April 2023; 16 (4): 185. https://doi.org/10.1158/1940-6207.CAPR-16-4-HFL Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Immune cells in colorectal cancer (by Juha P. Väyrynen et al via Cancer Immunology Research) A spatial survey of gene expression and proteomic changes in early-stage colorectal cancer reveals molecular and immunological features during tumorigenesis. Using digital spatial profiling and imaging mass cytometry, Roelands et al. analyzed normal, precancerous, and cancerous tissue samples from patients with early-stage disease and identified differentially expressed genes in the epithelium and stromal segments. They found that innate immune responses were activated early during malignant transformation, and there was a shift of immune cell composition from pro-inflammatory to immune-suppressive macrophage populations from normal tissue through dysplasia to cancer. These findings shed light on the stepwise progression of colorectal cancer and suggest that the approach could aid in identifying biomarkers for early detection and interception. Roelands J, … de Miranda NFCC. Gut. 2022 Nov 28:gutjnl-2022-327608. Small cell lung cancer (by Yale Rosen via Wikimedia Commons)... You do not currently have access to this content.

Melanoma antigens recognized by T cells and their use for immunotherapy.

Melanoma has been a prototype for cancer immunology research, and the mechanisms of anti-tumor T-cell responses have been extensively investigated in patients treated with various immunotherapies. Individual differences in cancer-immune status are defined mainly by cancer cell characteristics such as DNA mutations generating immunogenic neo-antigens, and oncogene activation causing immunosuppression, but also by patients' genetic backgrounds such as HLA types and genetic polymorphisms of immune related molecules, and environmental and lifestyle factors such as UV rays, smoking, gut microbiota and concomitant medications; these factors have an influence on the efficacy of immunotherapy. Recent comparative studies on responders and non-responders in immune-checkpoint inhibitor therapy using various new technologies including multi-omics analyses on genomic DNA, mRNA, metabolites and microbiota and single cell analyses of various immune cells have led to the advance of human tumor immunology and the development of new immunotherapy. Based on the new findings from these investigations, personalized cancer immunotherapies along with appropriate biomarkers and therapeutic targets are being developed for patients with melanoma. Here, we will discuss one of the essential subjects in tumor immunology: identification of immunogenic tumor antigens and their effective use in various immunotherapies including cancer vaccines and adoptive T-cell therapy.

Cancer Immunology Research: A Decade of Illumination and Innovation

<i>Cancer Immunology Research</i>: A Decade of Illumination and Innovation

Global Trends and Prospects Regarding Exosomes in Cancer Immunology Research Over the Past 10 Years.

Background: Exosomes and cancer immunology are both important areas of research for cancer treatment. As much effort has been made to explore the relationship between exosomes and cancer immunology, exosomes in cancer immunology have become a hotspot in medical research. Methods: We retrieved all relevant publications between 2011 and 2021 from the Web of Science and utilized Microsoft Excel 365, Citespace, Online Analysis Platform of Literature Metrology (http://bibliometric.com/) and software including VOS viewer to analyze and visualize the research result. Results: Of the 820 studies included, China published the most articles, followed by the USA. Cooperation between countries has progressed over the past decade. Shanghai Jiao Tong University and Oncotargets and Therapy were the institution and journal that published the most articles respectively. The most frequently cited article in this field, titled "Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver," was published in Nature Cell Biology. Keywords were divided into three: Mechanism research, treatment application research, and diagnosis and prognosis research of which the latter was the newest cluster. "Microenvironment," "PD-L1" and "M2 macrophage" were representative new keywords while "tumor suppressor" was the keyword cited most frequently. Conclusion: The publication trend shows that cooperation between different countries and institutions contributes to the development of this field. Researchers should continue to extend collaborations for further advances. The rising relative research interest indicated that this is a hot topic with great research potential. Macrophages polarization and PD-L1 application in tumor immunotherapy are worthy of further research. Hotspots will likely transfer from mechanistic research to clinical research, particularly for methods to increase the survival rate and improve the prognosis of cancer patients.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

CIMT 2022: Report on the 19th Annual Meeting of the Association for Cancer Immunotherapy

ABSTRACT The 19th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Europe’s cancer immunotherapy meeting, was the first in-person event organized by CIMT since the beginning of the COVID-19 pandemic. As a hybrid event from May 10–12, the meeting attracted 920 academic and clinical professionals from over 40 countries, who met to discuss the latest advances in cancer immunology and immunotherapy research. This report summarizes the highlights of CIMT2022.

Hiroshi Shiku, MD, PhD: In Memoriam (1943–2022)

Hiroshi Shiku, MD, PhD: In Memoriam (1943–2022)

In ovo model in cancer research and tumor immunology.

Considering cancer not only as malignant cells on their own but as a complex disease in which tumor cells interact and communicate with their microenvironment has motivated the establishment of clinically relevant 3D models in past years. Technological advances gave rise to novel bioengineered models, improved organoid systems, and microfabrication approaches, increasing scientific importance in preclinical research. Notwithstanding, mammalian in vivo models remain closest to mimic the patient’s situation but are limited by cost, time, and ethical constraints. Herein, the in ovo model bridges the gap as an advanced model for basic and translational cancer research without the need for ethical approval. With the avian embryo being a naturally immunodeficient host, tumor cells and primary tissues can be engrafted on the vascularized chorioallantoic membrane (CAM) with high efficiencies regardless of species-specific restrictions. The extraembryonic membranes are connected to the embryo through a continuous circulatory system, readily accessible for manipulation or longitudinal monitoring of tumor growth, metastasis, angiogenesis, and matrix remodeling. However, its applicability in immunoncological research is largely underexplored. Dual engrafting of malignant and immune cells could provide a platform to study tumor-immune cell interactions in a complex, heterogenic and dynamic microenvironment with high reproducibility. With some caveats to keep in mind, versatile methods for in and ex ovo monitoring of cellular and molecular dynamics already established in ovo are applicable alike. In this view, the present review aims to emphasize and discuss opportunities and limitations of the chicken embryo model for pre-clinical research in cancer and cancer immunology.

CD4+ T helper 2 cells suppress breast cancer by inducing terminal differentiation.

Cancer immunology research is largely focused on the role of cytotoxic immune responses against advanced cancers. Herein, we demonstrate that CD4+ T helper (Th2) cells directly block spontaneous breast carcinogenesis by inducing the terminal differentiation of the cancer cells. Th2 cell immunity, stimulated by thymic stromal lymphopoietin, caused the epigenetic reprogramming of the tumor cells, activating mammary gland differentiation and suppressing epithelial-mesenchymal transition. Th2 polarization was required for this tumor antigen-specific immunity, which persisted in the absence of CD8+ T and B cells. Th2 cells directly blocked breast carcinogenesis by secreting IL-3, IL-5, and GM-CSF, which signaled to their common receptor expressed on breast tumor cells. Importantly, Th2 cell immunity permanently reverted high-grade breast tumors into low-grade, fibrocystic-like structures. Our findings reveal a critical role for CD4+ Th2 cells in immunity against breast cancer, which is mediated by terminal differentiation as a distinct effector mechanism for cancer immunoprevention and therapy.