Intratumoral Immune Landscape: Immunogenicity to Tolerogenicity

Review Article

Austin J Clin Immunol. 2015; 2(1):1025.

Intratumoral Immune Landscape: Immunogenicity to Tolerogenicity

Abir K Panda, Sayantan Bose, Sreeparna Chakraborty, Kirti Kajal and Gaurisankar Sa*

Division of Molecular Medicine, Bose Institute, India

*Corresponding author: Gaurisankar Sa, Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054, India

Received: April 13, 2015; Accepted: September 05, 2015; Published: September 10, 2015


Immune system possesses distinct innate (less specific) and adaptive (more specific) branches which act in a collaborative way to eliminate cancer from the host. In spite of the presence of immune response, tumors develop in the body spontaneously through different immune escape strategies. During the progression of cancer, immune cells become paralyzed and altered. In tumor microenvironment both innate (macrophage and NK cells) and adaptive (CTLs and effector T cells) immune cells are unable to recognize and induce specific effector response against cancer to eradicate it. Tumor cells release different types of chemokines, cytokines, growth factors that can modulate immune cells to become tolerogenic and allow tumor cells to grow rapidly without any restriction. Immune cells also cannot discriminate the tumor antigens as they are concealed in stroma and are also less immunogenic. The immune cells thus become dormant and effective immune responses against tumors could not be elicited. Tumor cells exploit the plethora of immunosuppressive mechanisms which include abnormalities of antigen processing and presentation, induction of negative co-stimulatory signals that helps to establish tumor immune evasion. In addition, infiltration of T-regulatory cells, immature and tolerogenic Dendritic Cells (DCs), tumor-associated macrophages, and myeloid-derived stromal cells foster suppressive, tolerogenic condition. The understanding of different immune evasion mechanisms will help to design effective immunotherapies to overcome tolerogenic condition and elicit tumor regression.

Keywords: Immune cell dysfunction; Immunogenicity; Tolerogenicity; Tumor immune evasion; Tumor micro-environment


The innate and adaptive immune system work together to identify foreign pathogens as well as cancerous outgrowths in the host body and induces effective immune responses to eliminate them. But over the decades it has been a mystery, how tumor develops in the host in spite of the immune system’s potential to recognize and destroy them. In 1863 Rudolf Virchow first suggested that there was a functional relation between leukocyte infiltration and malignant growth. In 1957 Brunet and Thomas postulated the immune surveillance theory which stated that the immune system can counter attack developing tumor in a host [1]. However, this concept remained debatable due to the lack of experimental evidence. After a long period in 2003, new evidence indicated that immune system can eliminate tumors through immune surveillance [2,3]. During the process of tumor development, the tumor microenvironment, which is composed of tumor cells, immune cells, extracellular matrix, and stromal cells, produces certain key factors that helps in fostering tumor growth, proliferation and also promote metastasis. During tumor progression, modifications occur in certain signaling pathways of immune system that induces tumor immune tolerance and subsequently escape tumor immunity. In 2003 Robert Schreiber put forward the well accepted immune editing hypothesis which composed of three distinct phases: (i) Elimination, (ii) Equilibrium and (iii) Escape. In elimination or immune surveillance phase immune system can recognize and eliminate developing tumor thus protecting host against tumor. In equilibrium phase tumor cells and immune cells may enter into a dynamic equilibrium those results in tumor persistence. In escape phase tumor variants that escape from immune selection process of equilibrium stages develop into clinically apparent, highly metastatic and invasive tumors by avoiding the immune responses [4,5]. In tumor microenvironment the tumor cells employ certain strategies to escape immune response by modulating the immune cells so that they cannot recognize and eliminate them. When tumors become highly metastatic and invasive, the immune system becomes paralyzed and the improper immune response favors tumor progression. In this review we will discuss the tumor immune escape strategies and the role of immune cells in tumor immune evasion.

Tumor immune escape strategies

In tumor microenvironment tumor cells execute various strategies to evade the immune system and establishes immunogenic to tolerogenic environment.

Tumor-associated antigens (TAA) shows low immunogenicity

It is a well established that Tumor cell expressing Antigens (TAA) are not specifically neo-antigens that are exclusively expressed in tumor cells; rather they are tissue differentiation antigens also expressed in certain normal healthy cells [6]. Hence this creates the problem of generation of immune response against such tumor antigens. Tumor-associated antigens in early metastatic stage are embedded within the solid tumor [7]. The stromal cells near tumor site prevent efficient release of TAA in draining lymph nodes [8]. In late metastatic phase, efficient TAA release induces effective immunity; however immune tolerance to TAA develops by this stage and disables the function of APCs and other T-effector cells [9]. Like chronic inflammation, human tumorigenesis is a slow process that hampers early activation of NK cell and reshapes TAA specific priming to T cell specific tolerogenic responses [10] (Figure 1).