Immunogenic cell death in colon cancer prevention and therapy

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. The colonic mucosa constitutes a critical barrier and a major site of immune regulation. The immune system plays important roles in cancer development and treatment, and immune activation caused by chronic infection or inflammation is well-known to increase cancer risk.During tumor development, neoplastic cells continuously interact with and shape the tumor microenvironment (TME), which becomes progressively immunosuppressive. The clinical success of immune checkpoint blockade therapies is limited to a small set of CRCs with high tumor mutational load and tumor-infiltrating T cells. Induction of immunogenic cell death (ICD), a type of cell death eliciting an immune response, can therefore help break the immunosuppressive TME, engage the innate components, and prime T cellmediated adaptive immunity for long-term tumor control. In this review, we discuss the current understanding of ICD induced by antineoplastic agents, the influence of driver mutations, and recent developments to harness ICD in colon cancer. Mechanism-guided combinations of ICD-inducing agents with immunotherapy and actionable biomarkers will likely offer more tailored and durable benefits to patients with colon cancer. K E Y W O R D S cancer prevention, cancer therapy, colon cancer, immunogenic cell death 1 | INTRODUCTION Colorectal cancer (CRC) is a major cancer-related killer worldwide, with an increased incidence projected in many developing countries. The survival rate of metastatic CRC remains low at around 11%. 1 Most sporadic CRCs develop from benign preneoplastic polyp-like lesions following somatic inactivation of the APC tumor suppressor and progress with a series of genetic and epigenetic alterations accumulated over years or decades in KRAS/BRAF, SMAD/TGFBR2, p53, and PIKCA3 among others. 2 Existing research has highlighted critical interactions between the immune system and emerging tumor cells, and the complex changes in the tumor microenvironment (TME) during cancer progression toward immunosuppression and loss of immunosurveillance. 3 Cancer cell-intrinsic mechanisms are believed to play a key role in shaping local immune landscapes and therapeutic responses. 4 The breakthrough in immune checkpoint blockade (ICB), such as antibodies against programmed cell death-1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte associated antigen 4 (CTLA-4), 5,6 supports immune normalization or restoration in tumor control. 7 However, T-cell activating therapies have limited success in solid tumors. Induction of immunogenic cell death (ICD), a type of cell death eliciting an immune response, is,therefore, an attractive approach to break the immunosuppressive TME and re-establish immune surveillance by engaging both the innate and adaptive components. 8,9 ICD can be induced by a variety of chemopreventive agents, radiation, chemotherapeutics, and targeted therapies, and is shown to be critical for the antitumor effects in preclinical models through a...

MicroRNA-15a Carried by Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibits the Immune Evasion of Colorectal Cancer Cells by Regulating the KDM4B/HOXC4/PD-L1 Axis

“…Incidence and mortality rates of CRC are elevating in majority of the Asia-Pacific area, predominantly due to mounting urbanization and industrialization of countries and communities ( Ku et al, 2012 ). The immune system functions importantly in cancer progression and treatment, and immune response induced by chronic infection and inflammation may enhance the risk for cancers ( Ruan H. et al, 2020 ). Meanwhile, natural killer (NK) cells are a group of cells that could eliminate tumor cells and the release of cytokines, and NK cell-regulated production of interferon gamma (IFN-γ) is well known for its antiviral, immunoregulatory, as well as anti-tumor properties ( Cui et al, 2020 ).…”

eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis

“…Our data showed that mutant KRAS cooperates with p-4E and Myc to promote ISR-dependent Gln addiction, which is characterized by increased cell death, transcriptional heterogeneity, and surprisingly immune suppression upon deprivation. Hyperactivation of Wnt/Myc and mutant RAS/RAF are strongly associated with cancer aggressiveness including immunosuppressive TME, absence of TILs, and resistance to immune checkpoint inhibitors ( Ruan et al, 2020 ). Our data provide direct evidence that p-4E rewired translation and stress response is involved in this process through increased entropy or chaos ( Tarabichi et al, 2013 ; Hanselmann and Welter, 2016 ) and target selection during chronic metabolic adaptation and competition within tumor cells and with the TME ( Palm and Thompson, 2017 ; Andrejeva and Rathmell, 2017 ).…”

“…Myc, mutant RAS/RAF, or PIK3CA fuels abnormal growth by altering nutritional needs, including increased glutamine utilization. However, direct targeting a single driver, a single metabolic step, p-4E, or p-4E-BP1 has limited success in the clinic so far, due to complex resistance mechanisms encompassing compensatory pathway activation, metabolic bypasses, apoptosis resistance and immune suppression ( Dang et al, 2017 ; Pelletier et al, 2015 ; Truitt and Ruggero, 2016 ; Palm and Thompson, 2017 ; Ruan et al, 2020 ; Lito et al, 2013 ; Zhang and Yu, 2013 ). Our model supports that Myc-driven metabolic addiction likely goes beyond Gln to other nutrients and reducing agents such as arginine, cystine, and glutathione necessary to support increased biosynthesis ( Figure 7F ).…”

“…Elevated ISR in such tumors might therefore offer a therapeutic vulnerability. In fact, CRCs harboring mutant RAS/RAF or SPOP can be more effectively killed by drug combinations through catastrophic ISR associated with features of immunogenic cell death ( He et al, 2013 ; He et al, 2016a ; He et al, 2016b ; Li et al, 2017 ; Tan et al, 2019 ), which is believed to help achieve more durable cancer control in patients ( Ruan et al, 2020 ). The use of in-treatment and patient-derived models ( Silva-Almeida et al, 2020 ) will likely be important to capture dynamic transcriptional responses and biomarkers for tailoring therapeutic inventions.…”

Proteogenomic biomarkers in colorectal cancers: clinical applications

“…However, for patients with advanced CRC, the major interest is for new therapies and prognostic perspectives which are based on biological neoplastic features [5,13]. Recently, the utility of 'tailored therapy' has been proven in many studies, based on the fundamental paradigm that patients respond to biological therapies in different ways [27,28]. The term 'tailored therapy' is used to indicate a treatment based on patients' individual characteristics and specific cancer's histological pattern [8].…”