Tumor Immunology and Tumor Evolution: Intertwined Histories

In recent decades, cancer research has increasingly focused on understanding tumor heterogeneity to facilitate molecular classification and design personalized therapies. In this view, a critical yet still underexplored element is the tumor microenvironment (TME), composed of stromal, vascular, and immune cells embedded in the extracellular matrix (ECM) (1). These components interact dynamically, shaping tumor development and progression (2). The ECM, in particular, influences tumor angiogenesis and immune cell infiltration and activation, thereby impacting on pivotal aspects as hypoxia, cancer cell dissemination, and the tumor immune microenvironment (3). The latter represents the target of immunotherapeutic agents, which have revolutionised the treatment of certain cancer types and provided an efficacious option for subgroups of patients in recent decades (4)(5)(6). Nevertheless, a considerable number of patients fail to respond or experience adverse effects, underscoring the necessity for a more profound comprehension of the mechanisms underlying these processes and the identification of biomarkers that can effectively predict therapeutic outcomes. The principal objective of this Research Topic is to provide a platform for the publication of novel research findings pertaining to the mechanisms that regulate the crosstalk between the extracellular matrix (ECM) and the immune system. In addition, it aims to showcase valuable biomarkers and novel therapeutic targets that will facilitate the development of more effective patient management strategies.The recent advancements of immunotherapy have been promising for the treatment of cervical cancer (CC), however, the overall response rate suggested that the treatment is ineffective in subsets of patients. Gao and colleagues analyzed RNA-seq profiles from public datasets, identifying LAMA4 as a significantly overexpressed ECM-related gene (ERG) in CC compared to normal tissue. High LAMA4 expression correlated with poor overall and progression-free survival, as well as reduced immunotherapy response. Unexpectedly, LAMA4 was also detected in the nucleus, possibly due to ECM remodeling and nuclear translocation of fragments.activates integrin-mediated pro-survival signaling, fostering immune resistance. Thus, LAMA4 emerges as both a biomarker of poor prognosis and an active driver of an immunosuppressive microenvironment (7). ). This model stratified patients into high-and low-risk groups with significantly different survival outcomes, confirmed as an independent prognostic factor. High-risk patients displayed fewer immune cells, poorer clinical markers, and worse survival but greater sensitivity to drugs such as bortezomib. These findings suggest NET-related gene signatures as both prognostic markers and predictors of therapy response in MM (9). This Research Topic also encompasses reviews that offer insights into the highly complex characteristics of the TME.Mancini and colleagues reviewed the multifaceted roles of the ECM in cancer, emphasizing both its biomechanical and biochemical influences. They detailed how ECM stiffness and organization impact tumor progression, and how stromal and immune cells modulate ECM remodeling. The review highlighted ECM as not just a structural scaffold but a dynamic regulator of signaling pathways that drive cancer growth and therapy resistance (10). Shuhao Mei et al. explored hyperbaric oxygen therapy (HBOT) as a novel strategy to remodel the TME. HBOT increases tissue oxygenation, enhances mitochondrial activity, and generates reactive oxygen species that degrade collagen and fibronectin, softening the ECM. This facilitates immune and therapeutic cell penetration. HBOT also activates T and NK cells, stimulates matrix-degrading enzymes, reduces regulatory T cells, and suppresses HIF-1α, collectively promoting ECM breakdown and anti-tumor immunity. Their review suggests HBOT as a promising adjunct to conventional cancer therapies (11). The collection of articles in this Research Topic provides a comprehensive overview of the roles of the extracellular matrix (ECM) and immunity in cancer, highlighting how their interplay influences disease diagnostics, prognosis, and therapeutic strategies. The contributions introduce innovative methodologies and approaches that advance the identification of biomarkers capable of predicting responses to both conventional therapies and immunotherapies. Furthermore, the articles underscore the importance of deeper investigation into the tumor stroma and its individual components, offering novel perspectives for improving cancer diagnosis, understanding disease progression, and developing effective treatments.

Obituary - In Memoriam Per Brandtzaeg.

The immune system is a complex, dynamic and plastic network composed of various interacting cell types that are constantly sensing and responding to environmental cues. From very early on, the immunology field has invested great efforts to characterize the various immune cell types and elucidate their functions. However, accumulating evidence indicates that current technologies and classification schemes are limited in their ability to account for the functional heterogeneity of immune processes. Single cell genomics hold the potential to revolutionize the way we characterize complex immune cell assemblies and study their spatial organization, dynamics, clonal distribution, pathways, and crosstalk. This emerging field can greatly affect basic and translational research of the immune system. I will discuss how recent single cell genomic studies are changing our perspective of various immune related pathologies from cancer to autoimmune disease and neurodegeneration. Finally, I will consider recent and forthcoming technological and analytical advances in single cell genomics and their huge potential impact on the future of immunology research and immunotherapy. Citation Format: Ido Amit. The Power of ONE: Immunology in the age of single cell genomics [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr IA07.

The immune system is a complex, dynamic and plastic network composed of various interacting cell types that are constantly sensing and responding to environmental cues. From very early on, the immunology field has invested great efforts to characterize the various immune cell types and elucidate their functions. However, accumulating evidence indicates that current technologies and classification schemes are limited in their ability to account for the functional heterogeneity of immune processes. Single cell genomics hold the potential to revolutionize the way we characterize complex immune cell assemblies and study their spatial organization, dynamics, clonal distribution, pathways, and crosstalk. This emerging field can greatly affect basic and translational research of the immune system. I will discuss how recent single cell genomic studies are changing our perspective of various immune related pathologies from cancer to autoimmune disease and neurodegeneration. Finally, I will consider recent and forthcoming technological and analytical advances in single cell genomics and their huge potential impact on the future of immunology research and immunotherapy. Citation Format: Ido Amit. The power of ONE: Immunology in the age of single cell genomics [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA17.

Purpose. The clinical use of immune checkpoint inhibitors for multiple cancers has attracted attention in tumor immunology. Emerging evidence suggests that a better understanding of tumor immunology will lead to the development of new treatment strategies or the effective use of existing therapies. Histologically assessed tumor-infiltrating lymphocytes (hTIL) and programmed cell death 1 ligand 1 (hPD-L1) have been established as prognostic or predictive biomarkers in certain subsets of breast cancer. In addition, researchers have shifted their focus to the various immune cell subsets that make up TILs. However, the complexity of multiple types of immune cells in TIL or PD-L1 expressing cells is not fully understood. In this analysis, the immune cell fraction in breast cancer tissue and blood was evaluated by multicolor flow cytometry (FCM) to analyze the association between them and hTIL and hPD-L1. Methods. Forty-five tumor and 18 blood samples were collected from breast cancer patients. The leukocyte count, proportion of 11 types of immune cell fraction, and PD-L1 expression of each fraction were evaluated by FCM for both tumor and blood samples. The immune cell fractions are classified into the following categories based on the expression of cell surface markers: leukocyte, total T cell (total T), CD4+ T cell (CD4+ T), CD8+ T cell (CD8+T), B cell (B), monocyte/macrophage (Mo/Mϕ), nonclassical monocyte (CD16+Mo), myeloid-derived suppressor cells (MDSC), dendritic cells (DC), myeloid dendritic cells (mDC), natural killer cells (NK), minor NK, and natural killer T cells (NKT). hTIL, and hPD-L1 were evaluated by H-E staining and immunohistochemistry, respectively. Results. The mean density and interquartile range of tumor-infiltrating leukocytes were similar to those in previous report. For the immune cell fraction in the leukocytes of tumor tissue, the main population consisted of CD8+T and CD4+T, which showed a similar trend to that of blood. The proportions of DC, mDC, NK, and minor NK in tumor tissues were positively correlated with those of blood. When the percentage of each immune cell fraction of tumor tissue and that of blood were compared, the proportions of DC, mDC, and minor NK were significantly higher in tumor tissues than those in blood samples, and the proportions of CD4+T and NK were significantly lower in tumor tissue than in blood. No significant association was found between blood immune cell composition and hTIL or hPD-L1. High hTIL levels were associated with high leukocyte infiltration, high proportions of CD4+ T and CD8+ T, and a low proportion of NK and NKT in the tumor tissue. When PD-L1 positive cell percentage of each immune cell fraction was compared between the tumor tissue and blood, PD-L1 positive ratios were significantly higher in tumor tissue than in blood for all lineages except for lymphoid fractions. For tumor tissues, PD-L1 expression was high in Mo/Mϕ, CD16+Mo, MDSC, DC, and mDC. hPD-L1 positivity was associated with PD-L1 expression in Mo/Mϕ, CD16+Mo, DC, and mDC. Conclusion. Comprehensive analysis of the immune cell fractions revealed the immunological profile of breast cancer tissue represented by hTIL or hPD-L1. Our data indicate that hTIL not only reflects the amount of immune cell infiltration but also reflects a state in which acquired immunity is activated relative to innate immunity. Non-B cell antigen-presenting cell fractions such as Mo/Mϕ, CD16+ Mo, MDSC, DC, and mDC were primarily involved in the PD-L1 pathway in breast cancer microenvironments. In addition, hPD-L1 reflects PD-L1 expression in these immune cell fractions. Our data provide a basic understanding of the immune response in the breast cancer microenvironment and contribute to further development of tumor immunology. Citation Format: Toru Hanamura, Shigehisa Kitano, Hiroshi Kagamu, Makiko Yamashita, Mayako Terao, Banri Tsuda, Takuho Okamura, Nobue Kumaki, Katsuto Hozumi, Naoki Harada, Takaiki Iwamoto, Chikako Honda, Sasagu Kurozumi, Naoki Niikura. Systematic analysis of immune cell composition revealed immunological profile of breast cancer microenvironment represented by histologically assessed tumor-infiltrating lymphocyte and PD-L1 expression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-09.

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.

The immune system is a large network of organs, white blood cells, proteins (antibodies), and chemicals. This system works in concert to protect the body from foreign pathogens (bacteria, viruses, parasites, and fungi) that cause infection, disease, and illness. The human immune system works hard to stay healthy. Its task is to prevent the invasion of pathogens, destroy them or limit the extent of their damage if they enter. When the immune system is working properly, it can distinguish which cells are "own" and which substances are foreign to the body. It activates, mobilizes, attacks and kills foreign organisms that can harm human health. It is believed that the term "immunity" was used for the first time by Thucydides - a prominent ancient Greek philosopher, historian, political scientist and military leader. For the first time, he discovered the resistance of a recovered person to a recurrence of the disease. Since that time, hundreds of outstanding scientists have devoted their lives to the study of extremely complex processes that occur in the human immune system during invasion. The invention of the vaccine became a significant impetus in the development of immunology as a science. In 1885, Pasteur administered the first vaccine to a human, a young boy who had been repeatedly bitten by a rabid dog. Immunology made significant progress in the late 19th century due to rapid developments in the study of humoral immunity and cellular immunity. In 1903, a humoral component known as an opsonin was discovered that makes target bacteria suitable for phagocytosis. Particularly important was the work of Paul Ehrlich, who proposed the side chain theory to explain the specificity of the antigen-antibody reaction. His contribution to the understanding of humoral immunity was recognized by awarding a joint Nobel Prize in 1908 together with the founder of cellular immunology, the Russian zoologist Ilya Mechnikov, who first formulated the phagocytic theory in 1880. Modern immunologists, using the tools of molecular and cellular biology, genomics, and proteomics, will take a step towards preventing fatal diseases. The world is expected to witness a further explosion of knowledge in the field of immunology in the coming decades. Collaborative efforts across subjects such as tumor immunology, autoimmunity, and vaccinology are needed to develop strategies to protect against multiple diseases.

508 Generalizability of predictive versus prognostic indicators from published transcriptomic associations with tumor response to immune checkpoint inhibition

The origin and function of tumor-associated macrophages.

Chinese‐German Cooperation Group Tumor Immunology: Another inspiring Meeting in Deidesheim

Editorial: Perspectives on the landscape of immunology from Nikhil Joshi.

The past decade has seen immunotherapy rise to the forefront of cancer treatment. This Special Issue of <em>Cancers</em> aims to elaborate on the latest developments, cutting-edge technologies, and prospects in cancer immunology and immunotherapy. Seventeen exceptional studies, including original contributions and review articles, written by international scientists and physicians, primarily concerning the fields of tumor biology, cancer immunology, therapeutics, and drug development, comprise the main body of this Special Issue.

Although cancers develop and progress in immunocompetent hosts, immunological therapies for cancer have been proposed as alternative or complementary approaches to more standard therapy. It was initially thought that tumors were silent to the immune system, and that breaking immunological tolerance could result in immune-mediated tumor rejection. However, we have learned that cancer patients have preexisting immune responses against their tumor antigens which, nevertheless, fail to protect them, in part because of increased activity of the immune suppressor cells such as myeloid-derived suppressor cells (MDSC). Attempts to develop combinatorial therapies by depleting suppressor cells or blocking suppressor pathways and at the same time actively inducing immune responses in vivo or adoptively transferring tumor-specific T cells have largely failed. Very limited success has been achieved only against melanoma, using adoptive T-cell therapy, or prostate cancer, using a vaccine which improves patient survival but has no apparent inhibitory effect on disease progression. Further progress in the immunotherapy of cancer has been halted because of a poor understanding of the cellular components of the immune responses working together in favor of or against the tumors, as well as our inability to reliably reprogram immune responses towards the most effective phenotypes against cancer. This special issue is focused on understanding the escape mechanisms that malignant cells develop to hijack antitumor immune responses as well as strategies to overcome tumor escape. Four main areas that are covered in this issue include the following. Opposing Functions of the Immune System in Tumor Inhibition and Tumor ProgressionRobert Schreiber proposed the term “cancer immunoediting” in order to broadly describe the dual host-protecting and tumor-sculpting actions of the immune system that not only survey for, and eliminate, nascent malignant cells but also shape neoplastic disease through equilibrium and escape mechanisms. In this issue, M. Aris et al. discuss the dual function of the immune system in controlling and promoting tumor progression in cutaneous melanoma. They propose that tumor evolution is because of a continuous feedback between tumor cells and their environment, and thus different combinatorial therapeutic approaches can be implemented according to the tumor stage. A. Amedei et al. discuss recent knowledge on the contribution of T cells in oncogenesis. They review the different types, “friend or foe,” of T-cell response in gastric cancer. Tumor-Associated Modulation of Immune Checkpoint MoleculesUpon activation, T cells develop negative feedback regulatory mechanisms in order to avoid overstimulation. These include the expression of checkpoint molecules such as PD-1 and CTLA-4. T cells that recognize and respond to tumor antigens produce IFN-γ. A dual function of IFN-γ is the induction of apoptosis in target cells and upregulation of PD-L1 that interacts with PD-1 positive T cells, thereby resulting in the exhaustion of tumor-reactive T cells. Expression of CTLA-4 on activated T cells also results in T-cell anergy upon interaction with costimulatory molecules on DCs. S. Sapozink et al. describe new immunomodulatory approaches currently in the development pipeline, with focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described lymphocyte inhibitory targets, CTLA4 and PD-1. E. Rozali et al. provide an extensive review of the literature on the immunoregulatory role of PD-L2 in cancer-induced immune suppression and discuss the results of recent studies targeting PD-L2 in cancer. L. Cruz-Merino et al. discuss immune escape mechanisms in Hodgkin’s lymphoma (HL) and summarize the clinical, histological, pathological, and biological factors in HL, with special emphasis on the improvement of prognosis and their impact on treatment strategies. L. Farnault et al. introduce various mechanisms involved in the escape of hematological malignancies from NK-cell surveillance. These include NK-cell qualitative and qualitative deficiencies that occur through modulating the inhibitory and activating stimuli. Tumor-Induced Immune SuppressionMalignant cells produce cytokines and chemokines that facilitate the expansion or differentiation of immune suppressor cells such as Tregs, MDSC, and M2 macrophages. G. Zhou and H. Levitsky summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction. A particularly interesting notion that is touched upon involves tumor-independent treatment-induced homeostatic counter-regulation. M. Jadus et al. cover the escape mechanisms of bronchogenic lung cancer that must be overcome before they can be successfully treated. They also review the history of immunotherapy directed towards lung cancers. N. Hao et al. discuss the role of tumor-associated macrophages including M1 and M2 subsets during tumour progression and metastasis, highlighting the immunosuppressive role of M2 macrophages. V. Levina et al. investigate the role of indoleamine 2,3-dioxygenase (IDO1) in tumor escape and metastasis using 4T1 mammary carcinoma model. They show that IDO1 can not only suppress antitumour immune responses but also promote tumour cell proliferation. Improved Immunotherapeutic Strategies to Overcome Tumor EscapeImmunotherapy combined with blockade of immune suppressor pathways has been developed to overcome tumor-induced immune suppression. Cornelissen et al. discuss the interplay between a dual function of the immune responses against mesothelioma which can either inhibit or stimulate tumor growth and review the challenges associated with immunotherapy. They also discuss possible strategies and opportunities to overcome tumor escape. R. Casalegno-Garduño et al. analyze the expression of the leukemia-associated antigen receptor for hyaluronan acid-mediated motility (RHAMM) in patients suffering from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Their results suggest that immunotherapies like peptide vaccination or adoptive transfer of RHAMM-specific T cells might improve the immune response and the clinical outcome in AML/MDS patients. S.Wallner et al. summarize the current knowledge about the negative regulatory role of Cbl-b in T-cell activation and its potential therapeutic implications for cancer immunotherapy. H. Nagai et al. demonstrate that sorafenib-induced Th1 dominance can prevent the escape of tumor cells from the host immune system in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC).Overall, this special issue provides a well-rounded synopsis of representative research efforts addressing the issues related to “tumor escape and progression under immune pressure.”

It is well established that tumors evolve together with nonmalignant cells, such as fibroblasts, endothelial cells, and immune cells. These cells constantly entangle and interact with each other creating the tumor microenvironment. Immune cells can exert both tumor-promoting and tumor-protective functions. Detailed phenotypic and functional characterization of intra-tumoral immune cell subsets has become increasingly important in the field of cancer biology and cancer immunology. In this chapter, we describe a method for isolation of viable and pure immune cell subsets from freshly isolated murine solid tumors and organs. First, we describe a protocol for the generation of single-cell suspensions from tumors and organs using mechanical and enzymatic strategies. In addition, we describe how immune cell subsets can be purified by consecutive magnetic cell sorting and multi-parameter flow cytometry-based cell sorting.

The immune system is alerted to the presence of a pathogen through the activation of the innate immune system. The message is transmitted to the cells of the adaptive immunity through activated antigen-presenting cells. The development of specific immunity capable of eliminating the pathogen is orchestrated by cytokines and chemokines produced by the innate system. When everything functions optimally, the pathogen is eradicated and specific memory response is established. This finely tuned system can be subverted by pathogens, leading to disease. Immunity to cancer is orchestrated in the same way and it is now recognized that the early stages of tumour development are recognized by the cells of innate immunity that transmit this message to the cells of adaptive immunity. The molecules that alert the immune system and are also its targets are tumour antigens. Two important antigens for lung tumour-specific immunity are MUC1 and cyclin B1. We discuss how each molecule interacts with the innate and the adaptive immunity and the types of the immune responses that result for these interactions. We also discuss the state of immunosuppression of adaptive immunity in cancer patients due to chronic activation of the innate immune system.