Cancer immunotherapy: a promising dawn in cancer research.

Am J Blood Res 2020;10(6):375-385 www.AJBlood.us /ISSN:2160-1992/AJBR0123367 Review Article Cancer immunotherapy: a promising dawn in cancer research Banashree Bondhopadhyay1*, Sandeep Sisodiya1*, Atul Chikara1, Asiya Khan2, Pranay Tanwar2, Dil Afroze3, Neha Singh4, Usha Agrawal5, Ravi Mehrotra1, Showket Hussain1 Division of Molecular Oncology and Cellular & Molecular Diagnostics, National Institute of Cancer Prevention and Research (NICPR), Noida, India; 2All India Institute of Medical Science (AIIMS), New Delhi, India; 3Sher-i-Kashmir Institute of Medical Sciences Soura (SKIMS), Srinagar, Jammu and Kashmir, India; 4Department of Surgical and Perioperative Sciences, Umea University, Sweden; 5National Institute of Pathology, New Delhi, India. *Equal contributors. 1 Received September 29, 2020; Accepted December 4, 2020; Epub December 15, 2020; Published December 30, 2020 Abstract: Cancer is a highly proliferative disease, which is caused due to the loss of regulation of cell cycle and apoptosis, DNA damage, faulty repair system etc. The cancer microenvironment plays a pivotal role in disease progression as they contain different types of innate and adaptive immune cells. The most important molecules that establish a correlation between inflammation, innate immunity, adaptive immunity, and cancer are the molecules released by inflammatory cells in cancer microenvironment. These molecules secreted by the immune cells, which might activate a pro-tumorigenic and anti-tumorigenic response in cancer. In inflammatory microenvironment, the equilibrium state of immunosuppressive and immunostimulatory signals are important in tumor suppression. The immunotherapeutic approaches could be more effective in cancer treatment. However, advancement in immunobiology and cancer are improving the prospects of immunotherapy alone and/or in combination with the conventional therapies. Thus, the review attempts to highlight a promising and futuristic immunotherapeutic approach in combination with conventional treatment modalities. Keywords: Cancer, innate immunity, adaptive immunity, immunotherapies, oncolytic viruses and bacteria, tumorimmuno printing strategy Introduction The immune system plays a crucial role in infection. It acts in a cascade manner to counter the pathogenic response both by the innate and adaptive immune systems [1]. They work in tandem to protect the host by specialized immune cells acting in the tumor microenvironment [1, 2]. Innate immunity is the forefront protector in our body that generally protects the host by combating harmful microbes and helps in tissue repairing. Adaptive immunity comes into play when innate immunity breaks down and not capable to protect the body, which is based on antigen-specific receptors expressed on clonally expanded B and T lymphocytes. When innate immunity recognizes an infection or tissue injury, it recruits cells like macrophages, fibroblast, mast cell, dendritic cells, and leukocytes (monocytes and neutrophils) [2], which recognizes pathogenic determinants by PAMPs present on microbial nucleic acids, lipoprotein and carbohydrates. It also recognizes intracellular damage by DAMPs, released from injured tissues, with the help of intracellular and surface-expressed PRRs present on these cells. Furthermore, the activated PRRs then activate downstream transcription factors like NF-ĸB, AP-1, CREB, IRF etc. which gets activated and recruit leukocytes at the site of injury to repair microenvironment around the damaged tissue [2]. Thus, the activated leukocytes secrete proinflammatory cytokines (TNFα and IL1) and various chemokine’s that initiate the downstream effector cells, which are required for acute or chronic inflammation. Normally, anti-inflammatory cytokines are released after pro-inflammatory cytokines, which combat the effect of pro-inflammatory cytokines. Inflammation has Role of immunotherapy in carcinogenesis pro-tumorigenic effects as well as anti-tumorigenic effects which are used in cancer immunotherapy [3]. Host defense response normally shares the process of acute inflammation while chronic inflammation is a prolonged inflammation that can lead to cancer [4]. Nearly onethird of cancers are found to be linked with chronic inflammation [5]. A deregulated molecular pathways maintains the connection between the immune system and cancer in the tumor microenvironment; while considering the role of the immune system, inflammation and cancer are well documented [6]. This review provides holistic insights on the role of immune response in cancer and its futuristic manipulations highlighting the scope of immunotherapeutics in prevention and management of cancers. Origin of immunotherapy and cancer In 1909, Paul Ehrlich first suggested the idea of cancer immunotherapy and demonstrated that antibodies might have the ability to directly combat cancer cells [7]. Later, in 1950s, Burnet and Thomas hypothesized the concept of immune surveillance, according to which the immune system destroys malignant cells from primary cancer site before they become detectable tumors [8]. However, in 2001, Robert D Schreiber and his colleagues first used the term immunoediting in the light of cancer research to describe the phenomenon wherein tumors are characterized by the immune environment in which they form. In their study, they suggested that the immune response prohibited the development of carcinogen-induced sarcomas and spontaneous epithelial tumors. Besides, they also demonstrated that the tumor suppressor activity of the immune system is crucially reliant on IFN-γ, which partially helps in regulating the immunogenicity of tumor cells. Schreiber and his group provided in experimental evidence supporting the concept of immune surveillance for cancer. However, they had also suggested that tumors developed in the presence of healthy immune system are less immunogenic compared to those that are developed in an immunocompromised host makes the immune system paradoxical in favoring the eventual growth of tumors leading to the escape of the immune response that is better able to escape the immune response [9]. The immune system has four basic tumor eradica- 376 tion strategies: 1) The host is protected from virus-induced tumors by immune shedding of viral load. 2) In case of inflammation, the rapid clearance of pathogens and response of inflammation prevents the inflammatory microenvironment from advancing into the tumor. 3) The immune system identifies explicitly TAAs or molecules secreted by cells under stress to kill tumors. 4) The immune system identifies precancerous and cancerous cells and eradicates them before the damage occurs [10]. As we all know, nothing is perfect in this world likewise, our body’s defense mechanism is not as perfect as it should be able to eradicate the cancer cells. As a result, some tumor cells take advantage and escape the immune surveillance to promote proliferation of the cancer cells. In addition, these tum (...truncated)