Restoring the Immunity in the Tumor Microenvironment: Insights into Immunogenic Cell Death in Onco-Therapies (original) (raw)

Tumor-intrinsic determinants of immunogenic cell death modalities

OncoImmunology, 2021

The immune system can recognize tumor cells to mount antigen-specific T cell response. Central to the establishment of T cell-mediated adaptive immunity are the inflammatory events that facilitate antigen presentation by stimulating the expression of MHC and costimulatory molecules and the secretion of proinflammatory cytokines. Such inflammatory events can be triggered upon cytotoxic treatments that induce immunogenic cancer cell death modalities. However, cancers have acquired a plethora of mechanisms to subvert, or to hide from, host-encoded immunosurveillance. Here, we discuss how tumor intrinsic oncogenic factors subvert desirable intratumoral inflammation by suppressing immunogenic cell death.

Cancer immunogenicity, danger signals, and DAMPs: What, when, and how?

BioFactors, 2013

Cancer immunosurvelliance usually leads to formation of cancer cells that have been "immunoedited" to resist anti-tumor immunity. One of the consequences of immunoediting that is, reduced immunogenicity, is an important roadblock in revival of stable and long-lasting anti-tumor immune responses. Research done during the last decade has shown that emission by the dying cancer cells of immunomodulatory factors or damage-associated molecular patterns (DAMPs), which can act as danger signals, is a critical event in accentuating the immunogenicity of cancer cells, in response to a subset of anticancer treatments. Recent evidence has defined that an apoptotic cell death subroutine and its underlying biochemistry, which has been termed as "immunogenic cell death (ICD)" or "immunogenic apoptosis," is required for the efficient emission of DAMPs and inciting anti-tumor immunity. Here, we review the basic concepts of ICD, like cancer immunogenicity, danger signals, and DAMPs. Moreover, we discuss the emerging molecular links between endoplasmic reticulum (ER) stress, induction of a viral response-like gene expression, danger signals, and anti-tumor immunity. We envisage that along with ER stress-based trafficking of DAMPs (which is a "short-range communicator" of danger), the accompanying induction of a viral response-like gene expression and the secretion of anti-tumorigenic cytokines (acting as "long-range communicator" of danger) may become a crucial signature of ICD induction by anticancer therapy. V C 2013 International

Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy

Cancer and Metastasis Reviews, 2011

The success of some chemo-and radiotherapeutic regimens relies on the induction of immunogenic tumor cell death and on the induction of an anticancer immune response. Cells succumbing to immunogenic cell death undergo specific changes in their surface characteristics and release proimmunogenic factors according to a defined spatiotemporal pattern. This stimulates antigen presenting cells such as dendritic cells to efficiently take up tumor antigens, process them, and cross-prime cytotoxic T lymphocytes, thus eliciting a tumor-specific cognate immune response. Such a response can also target therapy-resistant tumor (stem) cells, thereby leading, at least in some instances, to tumor eradication. In this review, we shed some light on the molecular identity of the factors that are required for cell death to be perceived as immunogenic. We discuss the intriguing observations that the most abundant endoplasmic reticulum protein, calreticulin, the most abundant intracellular metabolite, ATP, and the most abundant nonhistone chromatin-binding protein, HMGB1, can determine whether cell death is immunogenic as they appear on the surface or in the microenvironment of dying cells.

Therapy-Induced Tumor Cell Death: Friend or Foe of Immunotherapy?

Frontiers in Oncology, 2021

Combinatory treatments using surgery, radiotherapy and/or chemotherapy together with immunotherapy have shown encouraging results for specific subsets of tumors, but a significant proportion of tumors remains unsusceptible. Some of these inconsistencies are thought to be the consequence of an immunosuppressive tumor microenvironment (TME) caused by therapy-induced tumor cell death (TCD). An increased understanding of the molecular mechanisms governing TCD has provided valuable insights in specific signaling cascades activated by treatment and the subsequent effects on the TME. Depending on the treatment variables of conventional chemo-, radio- and immunotherapy and the genetic composition of the tumor cells, particular cell death pathways are activated. Consequently, TCD can either have tolerogenic or immunogenic effects on the local environment and thereby affect the post-treatment anti-tumor response of immune cells. Thus, identification of these events can provide new rationales ...

An Emerging Approach for Combination Therapy of Cancer: The Role of Immunogenic Cell Death

Cell death resistance is a key feature of tumor cells. One of the main anti-cancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells.

Cell Death in the Tumor Microenvironment: Implications for Cancer Immunotherapy

Cells

The physiological fate of cells that die by apoptosis is their prompt and efficient removal by efferocytosis. During these processes, apoptotic cells release intracellular constituents that include purine nucleotides, lysophosphatidylcholine (LPC), and Sphingosine-1-phosphate (S1P) that induce migration and chemo-attraction of phagocytes as well as mitogens and extracellular membrane-bound vesicles that contribute to apoptosis-induced compensatory proliferation and alteration of the extracellular matrix and the vascular network. Additionally, during efferocytosis, phagocytic cells produce a number of anti-inflammatory and resolving factors, and, together with apoptotic cells, efferocytic events have a homeostatic function that regulates tissue repair. These homeostatic functions are dysregulated in cancers, where, aforementioned events, if not properly controlled, can lead to cancer progression and immune escape. Here, we summarize evidence that apoptosis and efferocytosis are explo...

Realizing the Clinical Potential of Immunogenic Cell Death in Cancer Chemotherapy and Radiotherapy

International Journal of Molecular Sciences

Immunogenic cell death (ICD), which is triggered by exposure of tumor cells to a limited range of anticancer drugs, radiotherapy, and photodynamic therapy, represents a recent innovation in the revitalized and burgeoning field of oncoimmunnotherapy. ICD results in the cellular redistribution and extracellular release of damage-associated molecular patterns (DAMPs), which have the potential to activate and restore tumor-targeted immune responses. Although a convincing body of evidence exists with respect to the antitumor efficacy of ICD in various experimental systems, especially murine models of experimental anticancer immunotherapy, evidence for the existence of ICD in the clinical setting is less compelling. Following overviews of hallmark developments, which have sparked the revival of interest in the field of oncoimmunotherapy, types of tumor cell death and the various DAMPs most prominently involved in the activation of antitumor immune responses, the remainder of this review i...

Current Approaches for Combination Therapy of Cancer: The Role of Immunogenic Cell Death

Cancers

Cell death resistance is a key feature of tumor cells. One of the main anticancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells.