Surface‐exposed calreticulin (ecto‐CRT) and secreted ATP are crucial damage‐associated molecular patterns (DAMPs) for immunogenic apoptosis. Inducers of immunogenic apoptosis rely on an endoplasmic reticulum (ER)‐based (reactive oxygen species (ROS)‐regulated) pathway for ecto‐CRT induction, but the ATP secretion pathway is unknown. We found that after photodynamic therapy (PDT), which generates ROS‐mediated ER stress, dying cancer cells undergo immunogenic apoptosis characterized by phenotypic maturation (CD80 high , CD83 high , CD86 high , MHC‐II high ) and functional stimulation (NO high , IL‐10 absent , IL‐1β high ) of dendritic cells as well as induction of a protective antitumour immune response. Intriguingly, early after PDT the cancer cells displayed ecto‐CRT and secreted ATP before exhibiting biochemical signatures of apoptosis, through overlapping PERK‐orchestrated pathways that require a functional secretory pathway and phosphoinositide 3‐kinase (PI3K)‐mediated plasma membrane/extracellular trafficking. Interestingly, eIF2α phosphorylation and caspase‐8 signalling are dispensable for this ecto‐CRT exposure. We also identified LRP1/CD91 as the surface docking site for ecto‐CRT and found that depletion of PERK, PI3K p110α and LRP1 but not caspase‐8 reduced the immunogenicity of the cancer cells. These results unravel a novel PERK‐dependent subroutine for the early and simultaneous emission of two critical DAMPs following ROS‐mediated ER stress.

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A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death.

Currently, it is widely acknowledged that a proactive anticancer immunosurveillance mechanism takes part in the rejection of neoplastic lesions before they progress towards a benign or malignant tumour. However in cases of very aggressive neoplastic lesions consisting of cells with high mutational diversity, cancer cell variants might be formed that are capable of evading host defence systems against uncontrolled proliferation and anticancer immunosurveillance. This is mainly accomplished through the exhibition of low immunogenicity, which is a particularly important stumbling block in the revival of long-lasting as well as stable anticancer immunity. Recently, it has emerged emphatically that inciting a cancer cell death routine, associated with the activation of danger signalling pathways evoking emission of damage-associated molecular patterns (DAMPs), markedly increases the immunogenicity of dying cancer cells. This cell death pathway has been termed "immunogenic cell death" (ICD). In the present review we introduce this concept and discuss its characteristics in detail. We also discuss in detail the various molecular, immunological and operational determinants of ICD.

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Immunogenic cell death

Vascular cell adhesion molecule-1 (VCAM-1) first attracted attention more than two decades ago as endothelial adhesion receptor with key function for leukocyte recruitment in term of cellular immune response. The early finding of VCAM-1 binding to melanoma cells, and thus a suggested mechanistic contribution to metastatic spread, was the first and for a long time the only link of VCAM-1 to cancer sciences. In the last few years, hallmarked by a growing insight into the molecular understanding of tumorigenicity and metastasis, an impressive variety of VCAM-1 functionalities in cancer have been elucidated. The present review aims to provide a current overview of VCAM-1 relevance for tumor growth, metastasis, angiogenesis, and related processes. By illustrating the intriguing role of VCAM-1 in cancer disease, VCAM-1 is suggested as a new and up to now underestimated target in cancer treatment and in clinical diagnosis of malignancies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.28927

Vascular cell adhesion molecule-1 (VCAM-1)—An increasing insight into its role in tumorigenicity and metastasis

Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host's immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.

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The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment.

Oxidative stress-induced calreticulin expression and translocation: new insights into the destruction of melanocytes

Tumor-induced angiogenesis has been shown to suppress immune responses. One mechanism is to suppress leukocyte-endothelial cell interaction by down-regulating the expression of adhesion molecules, such as intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and E-selectin on the tumor endothelium, which enables tumor cells to escape immune surveillance. Calreticulin (CRT), a chaperone protein mainly located in the endoplasmic reticulum, has been shown to exert anti-angiogenic activity and inhibit tumor growth. Here, we demonstrate that in addition to inhibiting angiogenesis, CRT also enhances the expression of both ICAM-1 and VCAM-1 on tumor endothelial cells. This expression results in enhanced leukocyte-endothelial cell interactions and increased lymphocyte infiltration into tumors. Therefore, combining intramuscular CRT gene transfer with intratumoral cytokine gene therapies significantly improves the antitumor effects of immunotherapy by markedly increasing the levels of tumor-infiltrating lymphocytes. This combined treatment increased the levels of infiltrating lymphocytes to those achieved using four times the cytokine dosage. The combined therapy also resulted in lower levels of immunosuppressive molecules and higher levels of activated T-cells in the tumor microenvironment than immunotherapy alone. In conclusion, this study describes a new antitumor mechanism of CRT that involves the up-regulation of tumor endothelial adhesion molecules and the enhanced infiltration of tumor-specific lymphocytes. Thus, CRT treatment can make tumor cells more vulnerable to immunotherapy and improve the therapeutic efficacy of immunotherapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.26339

Calreticulin promotes tumor lymphocyte infiltration and enhances the antitumor effects of immunotherapy by up-regulating the endothelial expression of adhesion molecules.

Background A majority of relapse cases have been reported in colorectal cancer patients due to cancer stem cell progenitors. The factors responsible for chemoresistance have yet to be discovered and investigated as CSCs have reported escaping from chemotherapy's killing action. Objective In this study, we have investigated the effects of HIF-1α and TGF-β2 in hypoxia conditions on the expression of GLI2, which is a potential factor for causing chemoresistance. Material and Methods. Colorectal samples of treated patients were collected from the Hospital Biological Sample Library. Culture of patient-derived TSs and fibroblasts was performed. The collected patient samples and cells were used for immunohistochemistry, quantitative PCR, and western blotting studies which were performed. Results It was reported that HIF-1α (hypoxia-inducible factor) and TGF-β2 secreted from cancer-associated fibroblasts (CAFs) synergistically work to express GLI2 in cancer stem cells. Hence, it increased the stemness as well as resistance to chemotherapy. Conclusion The HIF-1α/TGF-β2-mediated GLI2 signaling was responsible for causing chemoresistance in the hypoxia environment. High expressions of HIF1α/TGF-β2/GLI2 cause the relapsing of colorectal cancer, thus making this a potential biomarker for identifying the relapse and resistance in patients. The study uncovers the mechanism involved in sternness and chemotherapy resistance which will help in targeted treatment.

https://downloads.hindawi.com/journals/cmmm/2022/2032895.pdf

Hao Tien Wang

Papers

Calreticulin promotes tumor lymphocyte infiltration and enhances the antitumor effects of immunotherapy by up-regulating the endothelial expression of adhesion molecules.

Hypoxia Tumor Microenvironment Activates GLI2 through HIF-1α and TGF-β2 to Promote Chemotherapy Resistance of Colorectal Cancer

Anti-angiogenic therapy renders large tumors vulnerable to immunotherapy via reducing immunosuppression in the tumor microenvironment