Introduction:
Tumor immunity is defined as the control or prevention of disease aggression and it starts in the initial neoplastic transformation phase. It often occurs in the primary tumor site, but it has also been seen in distant tumor sites, bone marrow, and lymph nodes.
The endoplasmic reticulum has an established role in anti-tumor immunity. ER (endoplasmic reticulum) components are essential in deciding which antigenic peptides should be presented on the surface of the cancer cell to immune cells. Moreover, certain endoplasmic reticulum-resident proteins exit the endoplasmic reticulum and translocate to the surface under stress. Such translocation of endoplasmic reticulum proteins to the cells’ outside results in immune responses modulation in cancer, and autoimmunity.
What Are the Endoplasmic Reticulum and Its Function?
The endoplasmic reticulum is a dynamic structure that helps in many important cellular functions including protein folding, calcium storage, and lipid metabolism. It is a membranous network found in eukaryotic cells that helps proteins and other molecules’ movement. Proteins are arranged in the ribosomes and they are designated to be part of the cell membrane. The ribosomes help in assembling them and are attached to the endoplasmic reticulum, this will give a rough appearance. For protein synthesis, ER acts as the major site of synthesis and transport of proteins, protein folding, calcium storage, carbohydrate metabolism, and steroid and lipid synthesis. Performing these many functions and aiding in multitasking requires innumerable protein networks and coordination to respond inside the cell environment. After protein synthesis, translocation, or transport into the lumen of the endoplasmic reticulum, specific protein allotted for secretion should undergo folding and many modifications. This will be done with the help of folding enzymes and chaperones.
At times, though this complex mechanism of protein folding is carried out a small fragment of proteins will not attain the functional native form and they become aggregated or misfolded. They either persist in the endoplasmic reticulum or undergo the ERAD (endoplasmic reticulum-associated degradation) pathway which is regulated by the proteasome, ensuring that they do not enter circulation.
What Is the Role of the Endoplasmic Reticulum on Tumor Immunity?
In the process of cancer progression or malignant transformation, tumor cells undergo intrinsic, extrinsic stress, and endoplasmic reticulum stress. Multiple stress response pathways are used by the tumor cells to mitigate stress on the endoplasmic reticulum; therefore, they can survive and proliferate leading to the aggression of the disease and providing treatment resistance. Endoplasmic reticulum-associated degradation is one of the stress response pathways that has multiple steps and components contributing together to ensuring protein quantity and quality. ERAD has not only helped in tumor cell survival and creating stress responses but it has also been proven to regulate tumor immunity. ERAD is associated with cancer development and tumor immunity by promoting regulation of immune cell development and function, protein degradation, and participation in antigen presentation, and thus affects current cancer therapy.
Along with the role of the endoplasmic reticulum in immunity, ER protein content localization and its tumor-associated mutations have both advantageous and disadvantageous effects on anti-tumor immune responses. Alteration in endoplasmic reticulum protein localization can lead to immune-promoting effects. On the contrary, ER protein translocation has helped the uptake of apoptotic tumor cells thereby promoting anti-tumor T-cell immunity. The best role of ER in antigen peptide processing and peptide assembly into MHC (major histocompatibility complex) 1 and 2 molecules. This will eventually lead to the clonal expansion of tumor-reactive T-cells.
How Does the Endoplasmic Reticulum Influence Tumor Immunity?
Inside the calcium ion-rich boundaries of the ER, chaperones (protein group that help in protein folding), oxidoreductases (enzyme group helping electron transfer), and endoplasmic reticulum aminopeptidases (helps protein maturation) work together for benefitting the cellular state. It helps in the regulation of outside-world signaling. The fate of the cell is decided by chaperones such as GRP78 (glucose-regulating protein 78) and the stress gates (calcium channel that links cytosol and ER lumen) through their ability to control Ca2+ (calcium ion) release. These calcium ion alterations inside the ER will instigate cell stress and can trigger one or more UPR (unfolded protein response) coping mechanism pathways, which usually result in stressed cell recovery or non-inflammatory cell death. Nonetheless, solid tumors thrive in an environment with low oxygen and nutrients, which will subsequently trigger ER stress. GRP78 transcription which is triggered by stress in the endoplasmic reticulum clears the way for DNA (deoxyribonucleic acid) damage repair and chromatin remodeling. They also aid in survival in certain types of malignancies.
What Is the Significance of UPR and ER Stress in the Tumor Microenvironment?
UPR signaling is usually upregulated in the tumor microenvironment by the high metabolic rate of cancer cells, inflammatory factors, poor nutrient availability, and elevated hypoxia. In prostate cancer, transmissible ER stress (TERS) is a process in which tumor cells influence a UPR in the local tumor microenvironment, leading to a UPR in neighboring cells. This stress can also be seen in other cancers as well. Similar to inflammation, tumorigenicity is increased by UPAR in the tumor microenvironment and is related to proliferation, angiogenesis, stem-like phenotype, and survival during hypoxic conditions. If there is an increased UPR in neighbor cells then it helps in tumor development through Wnt (wingless-related integration site) signaling. The UPR also helps in the metastasis of cancer cells in circulation to the hypoxic regions. Increased UPR signaling is seen in bone metastases of lung, prostate, and breast cancers. Therefore reducing UPR signaling can reduce immunogenicity and improve the clearing of cancer cells. UPR activation has been reported to prevent apoptosis in prostate cancer cells.
Conclusion:
The endoplasmic reticulum and its specialized proteins contribute a crucial role in tumor immunity both indirectly and directly. The protein-folding capacity of the ER while infiltration of immune cells is disturbed by the tumor microenvironment causing continuous ER stress. The disabling of ER stress sensors and control of the UPR pathway can improve the anti-tumor immune responses. When the ER stress-related components present in tumor cells are targeted it can benefit in facilitating the cancer immunotherapies efficacy.
