Page 277 - Clinical Immunology_ Principles and Practice ( PDFDrive )

258 PART TwO Host Defense Mechanisms and Inflammation

These strategies include: are expressed on CTLs and to a less extent on NK cells, and
Latency. This involves minimizing viral gene expression and blocking of antibodies against these has revolutionized cancer
12
thereby avoiding detection. Examples include HSV in neurons, immunotherapy. In particular, IFN-γ upregulates PD-1
HIV in T cells, and EBV in B cells. ligands (PD-1L and PD-2L) on tumor cells, and their binding
Antigenic variation. Viruses possess the ability to rapidly mutate to PD-1 potently inhibits tumor-specific CTL activity.
its genome and produce escape variants that are no longer Anti-PD-1 monotherapy offers a high rate of sustained tumor
visible to CTLs. Such mutations were shown for MCMV regression in metastatic melanoma and is in clinical trials in
infection in mouse and HIV infection in humans. lung and breast cancers.
Infection of immune nonaccessible sites. Such inaccessible sites Antigenic mutation. Tumors can also avoid CTL activity by
include infection of the central nervous system by HSV or antigenic loss. This strategy takes the form of silencing or
rubella virus. mutating epitopes that are particularly immunogenic to CTL. 31
Production of viral defense molecules (immunoevasins). Many Broad-spectrum tumor-derived immune suppression. Tumors
viruses, including adenovirus and EBV, interfere with cytotoxic express a variety of membrane-bound and soluble factors
activity by producing proteins that either hinder Fas or TNF- that can suppress the immune response, including FasL, which
mediated killing or inhibit the function of antiviral cytokines, protects the tumor by inducing apoptosis in activated Fas-
such as IFN-α. A number of viruses, including EBV, produce expressing CTLs. This model is not universally accepted, and
homologs of antiapoptotic molecules, such as Bcl2, to inhibit a role for FasL in inducing the expression of inflammatory
killing by CTLs. Various members of the poxvirus family have cytokines is also possible. Tumors can also express TGF-β,
evolved homologs of the naturally occurring IL-18–binding which acts on CTLs and NK cells to inhibit their metabolism,
protein that inhibits IL-18 activity and NK-cell function. 32 proliferation, and expression of effector molecules, such as
Modulation of molecules involved in recognition. A widely utilized perforin and granzymes. TGF–β also acts on NK cells to
viral strategy to evade the cytotoxic response is to interfere downregulate the expression of NKG2D. Pharmaceutical
with antigen processing, presentation, or the expression of inhibitors of TGF-β signaling have been developed, and one
33
18
other molecules required for CTL recognition (Chapter 6). of them, galunisertib, is being tested in patients with cancer.
Several viruses, including adenovirus, downregulate MHC In addition, tumors can produce soluble decoy ligands, such
class I expression on the cell surface. This can be achieved by as MIC, which suppresses NKG2D function. CD73-mediated
a number of mechanisms. For example, adenovirus type 2 adenosine production also plays important immunosuppres-
E3 protein forms a complex with MHC class I to prevent sive roles in the tumor microenvironment. CD73 is a surface
antigens from being processed; MCMV gpm152 protein causes receptor expressed on many tumors and catalyzes extracellular
retention of the MHC class I molecules in the Golgi compart- adenosine monophosphate (AMP) into adenosine that can bind
ment; and CMV proteins US2 and US11 promote the rapid its receptor (A2AR) on NK cells/CTLs to suppress their activity.
degradation of newly synthesized MHC class I complexes. As such, A2AR and CD73 antagonists are being developed,
An alternative approach is to interfere with antigen processing, and their trials in cancer are ongoing. 18
either inhibiting the expression of the TAP protein, as is the
case for HSV, or producing proteins that are resistant to antigen Please check your eBook at https://expertconsult.inkling.com/
digestion by the proteasome, such as the EBNA-1 protein of for self-assessment questions. See inside cover for registration
EBV. This inhibition strategy is not restricted to MHC class details.
I, as both human CMV and MCMV express proteins that
inhibit the cell surface expression of NKG2D ligands.
Tumor Cells REFERENCES
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avoid cytotoxic activity (Chapter 77). Conversely, promoting the 2. Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes:
cytotoxic response either through specific tumor antigens, block- function, dysfunction and human pathology. Nat Rev Immunol
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I downregulation is associated with changes in the regulatory Opin Immunol 2016;40:110–16.
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