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Cancer Immunology

The healthy immune system employs a series of checkpoints in order to maintain self-tolerance or prevent collateral tissue damage during an immune response. Activation of CD8+ cytotoxic or CD4+ helper T cells occurs through the interaction of the T cell receptors (TCRs) with antigens on the surface of antigen-presenting cells (APCs) in the form of peptide antigen bound to major histocompatibility complex (MHC) molecules (1). In addition, binding of co-stimulatory signaling molecules on T cells (e.g., CD28, ICOS, GITR) with their receptors on APCs (e.g., CD80/CD86, ICOSL, GITRL) can also contribute to T cell activation (1). However, under certain circumstances, T cell receptor engagement is coupled with inhibitory signals that suppress T cell activation and response. These signals are generated by proteins involved in immune checkpoint control such as PD-1, CTLA-4, TIM-3, and LAG3 (2). PD-1 and CTLA-4 immune checkpoint proteins are commonly upregulated in tumor infiltrating T cells, bind their corresponding ligands, PD-L1 (B7-H1) / PD-L2 (B7-DC) and CD80/86 respectively, and downregulate the T cell response. Immune checkpoint ligands are often upregulated in cancer cells as a means to evade immune detection (3-5). Therefore, activating antitumor immunity by blocking immune checkpoint proteins has become the subject of intense research and drug development efforts toward cancer treatment (e.g., Anti-PD-1 immunotherapy) (6).

Below is a table of stimulatory and inhibitory receptor-ligand complexes, which mediate activation or dampening of the T cell response, respectively. Click on linked protein names for additional information and related product lists:

Cellular Response T cell Antigen presenting cell
Co-stimulatory CD28 B7-1 (CD80) or B7-2 (CD86)
CD40L CD40
TLT-2?** B7-H3
OX40 (CD134) OX40L
4-1BB (CD137) 4-1BBL
ICOS ICOSL
GITR GITRL
Co-inhibitory CTLA-4 B7-1 (CD80) or B7-2 (CD86)
PD-1 B7-H1 (PD-L1) or B7-DC (PD-L2)
Unknown B7-H3
Unknown B7-H4
Unknown VISTA
VISTA Unknown
LAG3 MHC-Class II
TIM-3 Galectin-9

**Myeloid cell-like transcript 2 (TLT-2) has been shown to express the putative receptor for B7-H3 (7,8). However its co-stimulatory nature and whether it, indeed, interacts with B7-H3 have been challenged (9). Hence the validity of this receptor-ligand interaction is a matter of debate.

There is also increasing interest in understanding the role of immunometabolism through potential therapeutic targets such as IDO and Arginase-1. IDO is an immunosuppressive enzyme involved in tryptophan degradation that is upregulated in many tumors. Arginase-1 is a ubiquitous enzyme highly expressed by myeloid derived suppressor cells (MDSCs) that are often recruited to the tumor microenvironment. In this context, Arginase-1 catalyzes the conversion of L-arginine to urea, thereby depriving T cells of nutrients that are essential for their activation and differentiation (10).

To understand the complex tissue microenvironment under both physiological and pathological conditions such as cancer, profiling immune checkpoint proteins and phenotypic markers is important. This can be achieved by using multiplexed assays for investigating multiple cancer immunotherapy targets and predictive biomarkers in limited and valuable patient samples. Below is a table of immune cell phenotyping markers. Click on linked protein names for additional information and related product lists:

Phenotypic Markers
CD3ε CD4
CD8 CD8α
CD31 CD36
CD44 CD45
CD45RO CD56 (NCAM)
CD68 CD79B
T-BET FOXP3
Arginase-1 GATA-3

Fluorescent multiplex immunohistochemistry (mIHC), enabling the detection of 6 or more proteins and biomarkers in formalin-fixed, paraffin-embedded (FFPE) tissue samples, is a valuable tool to study immuno-oncology. In mIHC as well as in single/dual-plex chromogenic IHC approaches, using validated antibodies against relevant targets is crucial to obtain reliable results. CST offers human-reactive and mouse-reactive IHC validated antibodies that enable investigators to get more information about biomarker expression, localization, interaction and disease context.

References:

  1. Malissen, B. et al., (2014) Integrative biology of T cell activation. Nat. Immuno 15, 790–797.
  2. Chen, L. et al., (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242.
  3. Pardoll, D. M. (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12, 252–264.
  4. Schildberg, F.A. et al., (2016) Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. Immunity 44, 955–972.
  5. Anderson, A.C. et al., (2016) Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 44, 989–1004.
  6. Sharma, P. et al., (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214.
  7. Hashiguchi M, et al., (2008) Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. Proc. Natl. Acad. Sci. U.S.A. 105(30), 10495–10500.
  8. Kobori H, et al., (2010) Enhancement of effector CD8+ T-cell function by tumour-associated B7-H3 and modulation of its counter-receptor triggering receptor expressed on myeloid cell-like transcript 2 at tumour sites. Immunology 130(3), 363–373.
  9. Leitner J, et al., (2009) B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. Eur. J. Immunol. 39(7), 1754–1764.
  10. Draghiciu O, et al., (2015) Myeloid derived suppressor cells-An overview of combat strategies to increase immunotherapy efficacy. Oncoimmunology 4(1), e954829.