Page 289 - Clinical Immunology_ Principles and Practice ( PDFDrive )

270 ParT TwO Host Defense Mechanisms and Inflammation

Tregs in the tumor are correlated with a poor prognosis and by Tregs can limit tissue damage but may enhance pathogen
survival. Treg cells are not only involved in solid tumors but also survival. This sort of compromise may not always be disadvanta-
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in hematological malignancies. For example, the architectural geous to the host. For example, in murine Leishmania major
pattern of Treg cells in follicular lymphomas is associated with infection, Tregs prevent complete eradication of the parasites,
the prognosis of the disease. Whether the elevated levels result which results in the persistence of low numbers of microbes
from migration of Tregs into the tumor or from an expansion on that have been proven to be essential for the development
the site is not clear, but evidence exists in support of both events. of T-cell memory and prevention of reinfection. However,
For example, ovarian tumor cells and infiltrating macrophages this delicate balance can be tipped in favor of the pathogen,
secrete the Treg-recruiting chemokine CCL22, which binds to which can be seen in the case of malaria and various viral infec-
CCR4 expressed by Tregs, and, in addition, many tumors produce tions such as human immunodeficiency virus (HIV). For
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TGF-β, which contributes to the maintenance of FOXP3 Tregs example, HIV-specific CD4 and CD8 T-cell responses are sub-
and may also induce FOXP3 expression in non-Treg cells within stantially suppressed by Tregs in vitro in most individuals with
the tumor microenvironment. It is now evident that both effector HIV infection. Taken together, future treatments, as well as vaccine
T cells and Tregs must be assessed in monitoring the efficacy of design, will need to take Tregs into account, and depending on
anticancer immunotherapy. 32 the pathogen in question, it might be necessary to reduce or
The involvement of Tregs in tumor immunity indicates that enhance the activity of Tregs to achieve a favorable outcome
antitumor immune responses can be provoked or enhanced by (see Table 18.3). 33
depleting Tregs in a host that is otherwise responding poorly.
Experimental mouse models have, indeed, demonstrated that TRANSLATIONAL RESEARCH
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simple depletion of CD25 Tregs with anti-CD25 antibody results
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in tumor eradication, and similar effects can be achieved with Manipulations of Foxp3 Tregs in animal models of, for example,
in vivo administration of agonistic anti-GITR, anti-CTLA-4– autoimmune disease, cancer, transplantation, and infection, have
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blocking antibodies or anti-CCR4 cell–depleting antibodies. shown a great potential for modulation of immunological diseases
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Depletion of CD25 T cells also enhances the effect of vaccination by this subset. The findings in animals have already started to
with tumor antigens. make their way into clinical practice and more is likely to come
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Pharmacological agents are another possible way of altering within the next 5–10 years. In cases when immunity needs to
the effector T cell/Tregs ratio. For example, fludarabine was shown be boosted, such as in cancer and during infection, the approach
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to selectively decrease the frequency of CD25 Tregs in patients is to identify molecules that inhibit function and differentiation
receiving chemotherapy. Conversely, previously used regimens, of Tregs as well as molecules that locally deplete them. Particularly,
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such as administration of exogenous IL-2, are now being reevalu- cancer immunotherapy has proven to be successful (Chapter
ated, since IL-2 may expand Tregs. As expected from the role of 77). Such examples in current therapy are CTLA-4–specific
Tregs in self-tolerance, a caveat of Treg-based therapies of cancer blocking antibody (ipilimumab; MDX-010/Yervoy; Bristol-Myers
is the possible development of autoimmunity that may depend Squibb, N.Y.); although CTLA-4 expression is not exclusive to
on the degree and period of in vivo systemic Tregs depletion, as Tregs, it is much more highly expressed and critical to their
well as the genetic make-up of the host. 32 suppressive function. In addition, recent studies have suggested
In addition to Foxp3-expressing Tregs, MSDCs are believed that in addition to blocking the function of CTLA-4, anti-CTLA-4
to have an important role in the establishment and maintenance antibodies may also deplete Tregs in the tumor environment,
of the tumor immunosuppressive environment, largely through but not in the periphery, because of antibody-dependent, cell-
their production of immunosuppressive cytokines, such as IL-10 mediated cytotoxicity. This depletions specificity to the tumor
and TGF-β, and reactive nitrogen and oxygen species. 26 environment may be attributed to a combination of high levels
of CTLA-4 expression and the presence of large numbers of
Infectious Disease phagocytic cells on the local area. Furthermore, other checkpoint
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Immune responses to infectious agents, such as bacteria and blockade strategies, such as those targeting the cell intrinsic
viruses, often result in tissue damage, which might be more immunosuppressive molecule PD-1 or its ligand PD-L1, have
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severe if it were not for the involvement of Tregs. On the downside, proven to be effective in early clinical trials. Additionally,
in many cases, Tregs can contribute to the development of combination therapies are of great interest. It has been found
chronic infections. As previously discussed, Tregs have the that anti-CTLA-4 treatment can lead to increased expression of
potential to directly respond to microbial products and are PD-L1 by the tumor itself, which may dampen the effect. Thus
believed to be engaged in suppressing responses to infectious adding both anti-CTLA-4 and anti-PD1 or PD-L1 may have
agents. A number of studies have shown that the outcome of greater benefits, as demonstrated by a recent phase I trial of
an infection partly hinges on the proper balance between effector anti-CTLA-4 (ipilimumab) plus anti-PD-1 (nivolumab) in patients
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T cells and Tregs. Adoptive transfer of Tregs prevents lethal with melanoma. Certain combinations may prove particularly
pneumonia in T cell–deficient mice infected with Pneumocystis effective, since they target different pathways. Again, in this case,
jiroveci, but at the expense of a deficient protective response and CTLA-4 may be acting primarily as a cell extrinsic suppressive
microbial clearance. Similarly, Tregs suppress Th1 responses in molecule on Tregs, and PD-1 may be acting in cis to suppress
mice infected with Helicobacter pylori, thereby limiting the PD-1–expressing CD4 or CD8 effector cells, and as a result, the
mucosal inflammation but resulting in a higher bacterial combination of the two may provide synergistic effects. As might
load. Human studies have shown that Tregs from carriers of H. be predicted, these types of immunomodulatory treatments can
pylori suppress responses to H. pylori antigens in vitro and have lead to severe autoimmune adverse events; however, further
increased frequencies of CD25 high T cells in both the stomach studies on both CTLA-4 and PD-1 and other potential check-
and the duodenal mucosa compared with Tregs from healthy points, such as B- and T-lymphocyte attenuator (BTLA), inducible
controls. Taken together, modulation of the infectious response T-cell costimulator (ICOS), and a range of other inhibitor or