Cancer Immunology Proteins

 Cancer Immunology Proteins Background

Cancer immunology

As cancer has become one of the most serious problems to human health, more and more researchers pay attention to cancer diagnosis and therapy. In normal condition, the immune system can recognize and destroy cancer cells in early development of cancer. However, once the immune system fails to recognize the alterations in cancer cells or cancer cells are actively evading the immune response, cancer will develop.

Cancer immunology is a branch of immunology which studies relationships and interactions between the immune system and cancer cells to understand how the immune system works or does not work against cancer. There are three major areas in cancer immunology, including the basic mechanisms of cancer immunity, engineering immune-based therapies, and developing clinical trials to study these new therapies. The recognition of cancer specific antigens is of particular interest in the field and can drive the development of effective targeted therapy, for example, developing new vaccines, new antibodies and tumor marker-based diagnostic kits for rapid diagnosis. As a primary manufacturer of recombinant proteins, Creative Biomart provides recombinant proteins of several sources, grades and formulations for cancer immunology research applications.


Avoiding immune detection

Tumor cells can avoid being recognized by the immune system (1) by migrating to immuno-privileged sites, (2) by altering their microenvironments in ways that reduce the survival, and impair the function, of immune cells, (3) by disrupting the presentation of tumor-cell antigens, and/or (4) by blocking costimulatory signals to antigen-presenting and immune-effector cells. Tumor cells can successfully grow in immuno-privileged sites such as the central nervous system and can create “metabolically hostile” microenvironments by altering local oxygen, pH, and amino acid levels in ways that impair the physical entry, survival, and activity of infiltrating immune cells. Malignant cells can also induce the generation of physical and molecular barriers to infiltrating immune cells via the synthesis of dense extracellular matrix and/or expression of immuno-suppressive molecules like Tim-3 on tumor-associated vasculature and/or galectins on surrounding stromal cells.

Normal- and tumor-cell peptides are presented to T-helper (Th) cells via HLA class I molecules and to cytotoxic T cells via HLA class II molecules. Antigen-presenting cells (APCs), including

DCs and monocytes/macrophages, normally present antigens to effector T cells via HLA class II molecules. Because myeloid leukemias arise from the same lineage as DCs and other APCs, (acute myeloid leukemia) AML cells are also able to present leukemic peptides to T cells on HLA class II complexes. Unfortunately, AML cells may behave like the immature DCs that promote immune tolerance (due to poor antigen-presentation) instead of functioning like the mature dendritic cells that promote immune clearance. Although converting AML cells into DCs is being explored for the development of therapeutic cancer vaccines, caution must be taken: the differentiation of AML cells into indoleamine 2,3-diosygenase (IDO)-expressing DCs has been shown to impair maturation of normal DCs and inhibit T-cell proliferation, potentially restricting their use.

Immunologic tolerance is the inability to mount an immune response against an antigen. Central tolerance – aka “natural” or “self tolerance” which is normal and protective – is established during development when T cells that can attack normal, self antigens (and potentially trigger autoimmune diseases) are deleted in the thymus. Unfortunately, malignant cells generate a peripheral tolerance to tumor antigens by inducing T-cell anergy, by triggering T-cell apoptosis, and/or by deviating Th1 cytotoxic T-cell-mediated responses toward Th2 B-cell-mediated responses that are less effective against cancer cells. Secretion of TGF-β is one way tumor cells distort immune-cell responses by directing Th1 cytotoxic T-cell responses toward Th2 humoral responses. AML cells also recruit, or induce formation of, regulatory T cells (Tregs) that suppress cytotoxic T cells. Through an IDO-dependent mechanism, AML cells promote conversion of CD4+CD25- T cells into CD4+CD25+ Tregs. Finally, tumors can permanently delete tumor-reactive T-cell clones by expression of death-inducing ligands or by chronic (repetitive) antigen stimulation which triggers activation-induced cell death.

Tumor cells resist immune-cell-mediated killing via the death receptor (Fas-mediated) and/or granule exocytosis (perforin- and granzyme-mediated) pathways. Tumor cells overexpress anti-apoptotic factors (FLIP, Mcl-1, Bcl-2), resist pro-apoptotic signals, and display mutations or defects in apoptotic pathways (Chiu, 1995; Reed, 2003). Tumor cells also neutralize death-inducing stimuli by shedding soluble receptors that act as decoys for death ligands like TRAIL and FasL. Strategies that can sensitize AML cells to T-cell or NK-cell killing include targeting anti-apoptotic factors that induce immune resistance. In a mouse model of colon cancer, treatment with a Nanog inhibitor decreased Mcl-1 levels and sensitized tumor cells to T-cell-mediated lysis. Small-molecule inhibitors of Bcl-2, TRAIL-receptor agonists, and IAP antagonists are currently being evaluated as anti-cancer agents in clinical trials.

Malignant cells express soluble and membrane-bound immuno-suppressive factors that disable (by inducing defects) or eliminate cancer-cell-reactive immune cells. Immune cells can become dysfunctional when cancer cells (1) secrete soluble factors, (2) express immune-checkpoint receptors and/or their ligands, (3) recruit, and/or induce formation of, immuno-suppressive cells, and (4) distort stromal and immune cells within cancer-cell microenvironments. Immuno-suppressive factors can inhibit immune-cell activation, maturation, proliferation, survival, cytotoxicity, and proinflammatory cytokine secretion as well as recruit immuno-suppressive cells and unfavorably polarize immune responses.

Cancer cells can express a variety of immuno-suppressive factors including TNF family ligands, immune-checkpoint receptors and their ligands, small molecules, enzymes, and cytokines. Cancer-cell expression of TNF family ligands (such as FasL, TRAIL, TNF) triggers T-cell apoptosis upon binding to TNF family receptors. By increasing cAMP, small molecules like prostaglandin E2, histamine, and epinephrine inhibit anti-tumor immune responses by decreasing IL-2 and IFN-γ production by T cells as well as IL-1β, IL-12, and TNFα production by monocytes and macrophages. expression of the immuno-suppressive enzymes IDO and arginase I by cancer cells, Tregs, and myeloidderived suppressor cells (MDSCs) impairs T-cell functions. By depleting tryptophan, IDO inhibits T-cell proliferation. Likewise, by depleting local L-arginine, arginase restricts T-cell proliferation and polarizes monocytes toward a suppressive M2-like phenotype. Cancer-cell secretion of cytokines like TGF-β, IL-10, and GM-CSF inhibits the proliferation of T cells and the release of pro-inflammatory cytokines.


Strategies to enhance tumor-cell immunogenicity

It is believed most cancers do, initially, trigger adaptive immune responses – evidenced by the presence of circulating tumor-reactive antibodies and immune cells. Over time, however, immunogenic cancer cells are eliminated, favoring the outgrowth of immune-escape variants. When considering how to target AML cells, possible immunologic strategies include increasing AML-cell immunogenicity and/or rendering AML cells less death-resistant (more susceptible to immunologic attack). Increasing the immunogenicity of AML LSCs may be important for eradicating therapy resistant “minimal residual disease” cells that can trigger relapse. AML LSCs are problematic because they are especially death-resistant and are better able to escape immune recognition and destruction than more mature leukemic blasts. As expected, poorly differentiated AML subtypes (M0) have been found to be less immunogenic than the more differentiated subtypes (M4-M5) as evidenced by weak in vitro alloimmune recognition of the poorly differentiated AML cells by T cells and their reduced expression of costimulatory molecules. In general, CSCs only weakly stimulate immune cells; thus ex vivo activation of a patient’s immune cells may require manipulation of stem-like cancer cells to improve their immunogenicity. Potential strategies to increase AML-cell immunogenicity – the ability to stimulate an adaptive immune response – include enhancing antigen-presentation by leukemia cells, blocking receptors like the “do not eat me” signals involved in immune escape, and inducing immunogenic tumor-cell death.


Cancer immunology reference

1. Lion E, Willemen Y, Berneman Z N, et al. Natural killer cell immune escape in acute myeloid eukemia[J]. Leukemia, 2012, 26(9): 2019-2026.

2. Calcinotto A, Grioni M, Jachetti E, et al. Targeting TNF-α to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy[J]. The Journal of Immunology, 2012, 188(6): 2687-2694.

3. van Luijn M M, Chamuleau M E D, Ressing M E, et al. Alternative Ii-independent antigen-processing pathway in leukemic blasts involves TAP-dependent peptide loading of HLA class II complexes[J]. Cancer immunology, immunotherapy, 2010, 59(12): 1825-1838.

4. Mapara M Y, Sykes M. Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance[J]. Journal of Clinical Oncology, 2004, 22(6): 1136-1151.

5. Curti A, Pandolfi S, Valzasina B, et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25− into CD25+ T regulatory cells[J]. Blood, 2007, 109(7): 2871-2877.