Cancer Immunoediting and beyond in 2021

Human cancer has been depicted as a non-linear dynamic system that is discontinuous in space and time, but progresses through different sequential states (Figure 1) [...]

Old and New Players of Inflammation and Their Relationship With Cancer Development

Pathogens or genotoxic agents continuously affect the human body. Acute inflammatory reaction induced by a non-sterile or sterile environment is triggered for the efficient elimination of insults that caused the damage. According to the insult, pathogen-associated molecular patterns, damage-associated molecular patterns, and homeostasis-altering molecular processes are released to facilitate the arrival of tissue resident and circulating cells to the injured zone to promote harmful agent elimination and tissue regeneration. However, when inflammation is maintained, a chronic phenomenon is induced, in which phagocytic cells release toxic molecules damaging the harmful agent and the surrounding healthy tissues, thereby inducing DNA lesions. In this regard, chronic inflammation has been recognized as a risk factor of cancer development by increasing the genomic instability of transformed cells and by creating an environment containing proliferation signals. Based on the cancer immunoediting concept, a rigorous and regulated inflammation process triggers participation of innate and adaptive immune responses for efficient elimination of transformed cells. When immune response does not eliminate all transformed cells, an equilibrium phase is induced. Therefore, excessive inflammation amplifies local damage caused by the continuous arrival of inflammatory/immune cells. To regulate the overstimulation of inflammatory/immune cells, a network of mechanisms that inhibit or block the cell overactivity must be activated. Transformed cells may take advantage of this process to proliferate and gradually grow until they become preponderant over the immune cells, preserving, increasing, or creating a microenvironment to evade the host immune response. In this microenvironment, tumor cells resist the attack of the effector immune cells or instruct them to sustain tumor growth and development until its clinical consequences. With tumor development, evolving, complex, and overlapping microenvironments are arising. Therefore, a deeper knowledge of cytokine, immune, and tumor cell interactions and their role in the intricated process will impact the combination of current or forthcoming therapies.

824 High quality neoantigens are immunoedited in long-term pancreatic cancer survivors

BackgroundCancer immunoediting predicts that T cells selectively kill tumor cells expressing immunogenic mutations (neoantigens) resulting in less immunogenic clones to outgrow in tumors.1 Although established through longitudinal studies of how tumors evolve in immune-proficient and -deficient mice,1 2 whether the human immune system naturally targets neoantigens to edit tumors, and the principles that identify the edited neoantigens, remains unclear.MethodsTo investigate if immune selective pressures on neoantigens alter how human tumors evolve, we longitudinally studied how 70 human pancreatic ductal adenocarcinomas (PDACs) - a poorly immunogenic cancer largely presumed to not be subject to immunoediting - evolved over 10 years. We use exome sequencing, neoantigen identification, and clonal reconstruction to compare how primary PDACs evolve to recurrence in rare long-term PDAC survivors previously shown to have more immunogenic tumors3 (n = 9 patients, n = 9 primary, 22 recurrent tumors), to short-term survivors with less immunogenic primary tumors (n = 6 patients, n = 6 primary, 33 recurrent tumors). To identify immunogenic “high quality” neoantigens, we use neopeptide-T cell functional assays and computational modeling to extend and apply a previously developed neoantigen quality model3 4 by predicting high quality neoantigens as arising from amino acid substitutions with sufficient antigenic distance from cognate wild-type peptides to differentially bind the MHC or activate a T cell.ResultsCompared to short-term survivors, we observe that long-term survivors evolve fewer recurrent tumors with longer latency, and distinct tissue tropism. To evaluate if differential immune pressures explained these differences, we discover that despite longer times to evolve, long-term survivors evolve genetically less heterogeneous tumors with fewer clones, fewer nonsynonymous mutations, and fewer neoantigens. To identify if high quality neoantigens are selectively edited in recurrent tumors of long-term survivors, we observe that neoantigens with greater antigenic distance (“less self”) are more depleted in primary and recurrent tumors of long- compared to short-term survivors. Furthermore, we find that long-term survivors evolve markedly fewer new neoantigens of strikingly lower quality, to indicate clones with high quality neoantigens are immunoedited.ConclusionsWe submit longitudinal evidence that the human immune system naturally edits neoantigens in PDAC. Furthermore, we present a model that describes how cancer neoantigens evolve under immune pressure over time, with implications for cancer biology and therapy. More broadly, our results argue that immunoediting is a fundamental cancer suppressive mechanism that can be quantified to predict tumor evolution.AcknowledgementsThis work was supported by NIH U01 CA224175 (V.P.B), a Stand Up to Cancer Convergence Award (B.D.G, V.P.B.), a Damon Runyon Clinical Investigator Award (V.P.B), and the Avner Pancreatic Cancer Foundation (A.J, A.G). Services by the Integrated Genomics Core were funded by the NCI Cancer Center Support Grant (P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.ReferencesShankaran V, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001;410:1107–1111.Matsushita H, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 2012;482:400–404.Balachandran VP, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 2017;551:512–516.Łuksza M, et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 2017;551:517–520.Ethics ApprovalThis study was performed in strict compliance with all institutional ethical regulations and approved by the institutional review boards of Memorial Sloan Kettering Cancer Center (MSK), the Garvan Institute of Medical Research, and the The Johns Hopkins Hospital (JHH). We obtained informed consent from all patients.

Redefining innate natural antibodies as important contributors to anti-tumor immunity

Myeloid, T and NK cells are key players in the elimination phase of cancer immunoediting, also referred to as cancer immunosurveillance. However, the role of B cells and NAbs, which are present prior to the encounter with cognate antigens, has been overlooked. One reason is due to the popular use of a single B cell-deficient mouse model, muMT mice. Cancer models using muMT mice display a similar tumor burden as their WT counterparts. Empirically, we observe what others have previously reported with muMT mice. However, using two other B cell-deficient mouse models (IgHELMD4 and CD19creDTA), we show a 3 to 5-fold increase in tumor burden relative to WT mice. In addition, using an unconventional, non-cancer-related, immune neoantigen model where hypoxic conditions and cell clustering are absent, we provide evidence that B cells and their innate, natural antibodies (NAbs) are critical for the detection and elimination of neoantigen-expressing cells. Finally, we find that muMT mice display anti-tumor immunity because of an unexpected compensatory mechanism consisting of significantly enhanced Type 1 interferon (IFN)-producing plasmacytoid dendritic cells (pDCs), which recruit a substantial number of NK cells to the tumor microenvironment compared to WT mice. Diminishing this compensatory pDC-IFN-NK cell mechanism revealed that muMT mice develop a 3 to 5-fold increase in tumor burden compared to WT mice. In summary, our findings suggest that NAbs are part of an early defense against not only microorganisms and dying cells, but precancerous cells as well.

Neutrophil Extracellular Traps (NETs) in Cancer Invasion, Evasion and Metastasis

The present review highlights the complex interactions between cancer and neutrophil extracellular traps (NETs). Neutrophils constitute the first line of defense against foreign invaders using major effector mechanisms: phagocytosis, degranulation, and NETs formation. NETs are composed from decondensed nuclear or mitochondrial DNA decorated with proteases and various inflammatory mediators. Although NETs play a crucial role in defense against systemic infections, they also participate in non-infectious conditions, such as inflammation, autoimmune disorders, and cancer. Cancer cells recruit neutrophils (tumor-associated neutrophils, TANs), releasing NETs to the tumor microenvironment. NETs were found in various samples of human and animal tumors, such as pancreatic, breast, liver, and gastric cancers and around metastatic tumors. The role of the NETs in tumor development increasingly includes cancer immunoediting and interactions between the immune system and cancer cells. According to the accumulated evidence, NETs awake dormant cancer cells, causing tumor relapse, as well as its unconstrained growth and spread. NETs play a key regulatory role in the tumor microenvironment, such as the development of distant metastases through the secretion of proteases, i.e., matrix metalloproteinases and proinflammatory cytokines. NETs, furthermore, directly exacerbate tumor aggressiveness by enhancing cancer migration and invasion capacity. The collected evidence also states that through the induction of the high-mobility group box 1, NETs induce the epithelial to mesenchymal transition in tumor cells and, thereby, potentiate their invasiveness. NET proteinases can also degrade the extracellular matrix, promoting cancer cell extravasation. Moreover, NETs can entrap circulating cancer cells and, in that way, facilitate metastasis. NETs directly trigger tumor cell proliferation through their proteases or activating signals. This review focused on the pro-tumorigenic action of NETs, in spite of its potential to also exhibit an antitumor effect. NET components, such as myeloperoxidase or histones, have been shown to directly kill cancer cells. A better understanding of the crosstalk between cancer and NETs can help to devise novel approaches to the therapeutic interventions that block cancer evasion mechanisms and prevent metastatic spread. This review sought to provide the most recent knowledge on the crosstalk between NETs and cancer, and bring more profound ideas for future scientists exploring this field.

Modeling Cancer Immunoediting in Tumor Microenvironment with System Characterization through the Ising-model Hamiltonian

Background and Objective: Cancer Immunoediting (CI) describes the cellular-level interaction between tumor cells and the Immune System (IS) that takes place in the Tumor Micro-Environment (TME). CI is a highly dynamic and complex process comprising three distinct phases (Elimination, Equilibrium and Escape) wherein the IS can both protect against cancer development as well as, over time, promote the appearance of tumors with reduced immunogenicity. We present an agent-based model for the biological system in the TME, intended to simulate CI. Methods: Our model includes agents for tumor cells and for elements of the IS. The actions of these agents are governed by probabilistic rules, and agent recruitment (including cancer growth) is modeled via logistic functions. The system is formalized as an analogue of the Ising model from statistical mechanics to facilitate its analysis. The model was implemented in the Netlogo modeling environment and simulations were performed to verify, illustrate and characterize its operation. Results: Our model is capable of generating the three phases of CI; it requires only a couple of control parameters and is robust to these. We demonstrate how our simulated system can be characterized through the Ising-model energy function, or Hamiltonian, which captures the “energy” involved in the interaction between agents and presents it in clear and distinct patterns for the different phases of CI. Conclusions: The presented model is very flexible and robust, captures well the behaviors of the target system and can be easily extended to incorporate more variables such as those pertaining to different anti-cancer therapies. System characterization via the Ising-model Hamiltonian is a novel and powerful tool for a better understanding of CI and the development of more effective treatments.

Cancer immunoediting by melanocyte differentiation antigen-specific T cells determines response to immune checkpoint inhibition

T cells are critical in cancer immune surveillance but they can also shape tumor immunogenicity, described as cancer immunoediting. Melanoma patients commonly harbor T cells recognizing melanocyte differentiation antigens (MDAs). However, the roles of MDA-specific T cells in shaping melanoma immunogenicity and the response to immune checkpoint inhibition remain elusive. Here, we prospectively profiled peripheral CD8+ T cells from 27 stage IV patients before initiation of checkpoint inhibitor therapy. Clinical failure was associated with increased MDA-specific CD8+ T cells and reduced tumor MDA expression pretreatment. In nonresponders, decreased tumor MDA expression was concomitant with a dedifferentiated melanoma phenotype. We confirmed in 30 stage III patients that individuals with relapse disease during adjuvant anti-PD-1 therapy demonstrated a significantly higher incidence of dedifferentiated tumors pretreatment than individuals without recurrence. Thus, MDA-directed CD8+ T cells are associated with a dedifferentiated phenotype and reduced clinical response to checkpoint inhibitor therapy suggesting immunoediting as an important resistance mechanism.

Stochastic Simulation on a Minimal Model of Cancer Immunoediting Theory

In this paper, we explore the interplay between tumor cells and the human immune system, based on a deterministic mathematical model of minimal interactions by transforming it to stochastic model using a continuous-time Markov chain, where time is continuous but the state space is discrete. Furthermore, we simulate the stochastic basin of attraction to verify the behavior of the three critical points of interest in the deterministic system. Moreover, the stochastic simulations exemplify the cancer immunoediting theory in its three phases of development: elimination, equilibrium and escape. We extend the minimum model proposed in [DeLisi & Rescigno, 1977] to include a term of immunotherapy by lymphocyte injection, and we simulate two treatment regimes, equilibrium and escape, under several schemes.