Question

1. What are some of the mechanisms by which tumors may evade the immune response?

Answer 1

Answer - Tumor escape happens when the immune system is not capable enough to eradicate tumors, which carry accumulated genetic and epigenetic alterations and use several mechanisms to be the victorious of the immunoediting process. Following the tumor outgrowth, clinical manifestations of cancer develop.

The mechanisms interfering in shaping robust antitumor immune responses are mainly divided into the following categories: (1) defective tumor antigen processing or presentation, (2) lack of activating mechanisms, (3) inhibitory mechanisms and immunosuppressive state, and (4) resistant tumor cells.

Defects in Tumor Antigen Processing, Presentation, and Recognition-

As mentioned before, some categories of tumor antigens are shared with the antigens of normal cells, which have “self” nature and are recognized by low-affinity T cellsagainst self-antigens. If the antigen/MHC-I complexes are abandoned, the condition induced through vaccines, the low-affinity T cells become capable of eliminating tumor cells.

The tumor antigens might be present in a new form due to the genetic instability, mutation of the tumor and escape from immune system. Epitope-negative tumor cells remain hidden and consequently resistant to the immune rejection. They have been developed following the elimination of epitope-positive tumor cells,86 similar to Darwin's theory of natural selection. Loss of MHC-I during progression and metastasis of the tumor contributes to immune escape as well.

Similarly, T cells give rise to the number of MHC-I–negative tumors by eradicating MHC-I–positive tumors. Although immunotherapy leads to the upregulation of MHC-I, and IFN-γ increases the expression of MHC-I as well, this does not necessarily lead to tumor rejection. Antigen processing machinery in DC is the other factor that might be decreased due to the tumor progression. However, it is reversible by incubation with cytokines such as TNF-α, IFN-γ, IL-6, IL1β, and IFN-α.

Lack of Activating Mechanisms -

In addition to the main signal transduced through presentation of peptide/MHC-I complex to the TCRs, costimulatory signals are required to recognize the tumor antigen. In the case of lacking costimulatory molecules such as CD28 on the surface T cells and CD80 on the surface of APCs, T cell activation does not occur.

Tumor cell–induced apoptosis of T cells results in decreased immune responses against cancer. It is executed by interaction of Fas and FasL on the surface of T cells and tumor cells, respectively.94 Tumor cells by overexpression of gangliosides also inhibit T cell proliferation and cytokine secretion.

Inhibitory Mechanisms and Immunosuppressive State -

When the costimulatory signals are replaced by inhibitory signals, T cell activation fails. CTLA-4 is an inhibitory molecule on the surface of T cells, which competes with CD28 to bind the B7 proteins, CD80 and CD86. There is also evidence of development of inhibitory mechanisms by CTLA-4 in the absence of CD28. In this case, CTLA-4 transduces a negative signaling independent of CD28, resulting in rapid T cell inhibition. However, the competitive function of CTLA-4 with the CD28 costimulatory function leads to T cell anergy.

There are some inhibitory immune cells, such as Tregs and MDSC, that can alter the outcomes of an immune response against tumors. As mentioned previously, Tregs are CD4+ CD25 high FOXP3+ T cells, which are increased in tumors and the peripheral circulation of patients with cancer, probably due to the self-nature of tumor antigens and to induce tolerance against them.

Tregs perform their immunosuppressive activities through different approaches such as production of inhibitory cytokines like IL-10 and TGF-β1, enzymatic degradation of ATP to immunosuppressive adenosine,99modulation of apoptosis of T cells by Fas/FasL pathway, and production of granzyme/perforin.

Resistant Tumor Cells -

As the pathologic process of cancer progresses, more genomic instabilities are accumulated in the tumor cells, which make them more resistant to immune responses and immunotherapy. Cancer stem cells are the other cause of resistance to immunity and cancer treatment, since they are multipotent cells, well-preserved from the immune system, with self-renewal capability, and live for a long time.