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Review
. 2010 Jul;10(7):1019-35.
doi: 10.1517/14712598.2010.482207.

Inhibiting the inhibitors: evaluating agents targeting cancer immunosuppression

Theresa L Whiteside  1
Affiliations
Review

Inhibiting the inhibitors: evaluating agents targeting cancer immunosuppression

Theresa L Whiteside. Expert Opin Biol Ther. 2010 Jul.

Abstract

Importance of the field: Immunotherapy of cancer has not improved disease-free or overall patient survival. The lack of concordance between immunological and clinical responses in cancer immunotherapy trials is thought to result from the pervasive presence of tumor-driven immune suppression that allows tumor to escape and that has not been adequately targeted by current therapies.

Areas covered in this review: Because multiple mechanisms of tumor induced suppression have been identified and shown to contribute to tumor escape, the opportunity arises to interfere with these mechanisms. A range of known tumor-derived inhibitors can now be blocked or neutralized by biologic or metabolic agents. Used alone or in combination with each other or with conventional cancer therapies, these agents offer novel therapeutic strategies for the control of tumor escape.

What the reader will gain: This review deals with currently available inhibitors for counteracting tumor immune escape. The restoration of effective anti-tumor immunity in patients with cancer will require new approaches aiming at: i) protection of immune cells from adverse effects of myeloid-derived suppressor cells, regulatory T cells or inhibitory factors thus enhancing effector functions; and ii) prolonging survival of central memory T cells, thus ensuring long-term protection.

Take home message: Inhibitors of mechanisms responsible for tumor escape could restore anti-tumor immune responses in patients with cancer.

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Conflict of interest statement

Declaration of interest

This paper has been sponsored by NIH Grants PO1-CA109688 to TLW and RO1-CA112643 to D. Shin (TLW co-investigator).

Figures

Figure 1
Figure 1. Strategies for countering tumor-induced immune suppression
A. Inhibition of tumor-induced inhibitors. The tumor presents antigens to DC using the MHC class I or class II molecules. In the suppressive tumor environment, anti-tumor immune responses are inhibited by a variety of mechanisms. To restore anti-tumor immune responses and to counter tumor-induced inhibitory effects, it is now possible to block these mechanisms using biologic or non-biologic agents. Blocking of inhibitory pathways or signals is indicated by solid black lines. The numbers refer to various available inhibitors as follows: 1) mAbs specific for growth factor receptors on tumor cells or for inhibitory receptors such as PD-L1; 2) interference with Treg induction by altering the DC program; 3) neutralization of Treg-derived or DC-derived factors/molecules with mAbs or inhibitors; 4) depletion of Treg and/or MDSC with antibodies, immunotoxins or drugs such as Sunitinib; 5) blocking activity of MDSC-derived immunoinhibitory factors with metabolic inhibitors; 6) inhibition of MDSC recruitment from the bone marrow or their activity with mAbs or inhibitors specific for tumor-derived factors; 7) T-cell checkpoint blockade with mAbs such as anti-CTLA-4 or others targeting receptors that can bind tumor-derived inhibitory ligands. Metabolic antagonists are available to block activities of IDO, PGE2 and adenosine (Table 3). B. Activation of immune cells in the tumor microenvironment, their replacement via adoptive transfers or cytokine-mediated extension of their survival. Solid arrows indicate activating signals targeting TLRs or other receptors and co-stimulatory molecules, e.g., APC-associated CD40, expressed on immune cells. Dashed arrows indicate the possibility that tumor cells, MDSC and Treg, all of which express TLRs, may be also activated with adjuvants targeting these receptors. The adoptively transferred T cells with anti-tumor activity re-populate the lymphocyte pool. Chemokines and cytokines such as IL-7 or IL-15 promote T-cell growth, protect them from apoptosis and prolong their survival. In A and B, thin arrows indicate that CTL and CD4+ effector T cells proliferate/differentiate into competent anti-tumor effector T cells and memory T cells as a result of immune activation or inhibition of tumor-derived factors.
Figure 1
Figure 1. Strategies for countering tumor-induced immune suppression
A. Inhibition of tumor-induced inhibitors. The tumor presents antigens to DC using the MHC class I or class II molecules. In the suppressive tumor environment, anti-tumor immune responses are inhibited by a variety of mechanisms. To restore anti-tumor immune responses and to counter tumor-induced inhibitory effects, it is now possible to block these mechanisms using biologic or non-biologic agents. Blocking of inhibitory pathways or signals is indicated by solid black lines. The numbers refer to various available inhibitors as follows: 1) mAbs specific for growth factor receptors on tumor cells or for inhibitory receptors such as PD-L1; 2) interference with Treg induction by altering the DC program; 3) neutralization of Treg-derived or DC-derived factors/molecules with mAbs or inhibitors; 4) depletion of Treg and/or MDSC with antibodies, immunotoxins or drugs such as Sunitinib; 5) blocking activity of MDSC-derived immunoinhibitory factors with metabolic inhibitors; 6) inhibition of MDSC recruitment from the bone marrow or their activity with mAbs or inhibitors specific for tumor-derived factors; 7) T-cell checkpoint blockade with mAbs such as anti-CTLA-4 or others targeting receptors that can bind tumor-derived inhibitory ligands. Metabolic antagonists are available to block activities of IDO, PGE2 and adenosine (Table 3). B. Activation of immune cells in the tumor microenvironment, their replacement via adoptive transfers or cytokine-mediated extension of their survival. Solid arrows indicate activating signals targeting TLRs or other receptors and co-stimulatory molecules, e.g., APC-associated CD40, expressed on immune cells. Dashed arrows indicate the possibility that tumor cells, MDSC and Treg, all of which express TLRs, may be also activated with adjuvants targeting these receptors. The adoptively transferred T cells with anti-tumor activity re-populate the lymphocyte pool. Chemokines and cytokines such as IL-7 or IL-15 promote T-cell growth, protect them from apoptosis and prolong their survival. In A and B, thin arrows indicate that CTL and CD4+ effector T cells proliferate/differentiate into competent anti-tumor effector T cells and memory T cells as a result of immune activation or inhibition of tumor-derived factors.
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References

    1. Whiteside TL. Immune responses to malignancies. J Allergy Clin Immunol. 2010;125:S272–83. - PMC - PubMed
    1. Sahin U, Tureci O, Pfreundschuh M. Serological identification of human tumor antigens. Curr Opin Immunol. 1997;9:709–16. - PubMed
    1. Lee PP, Yee C, Savage PA, et al. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med. 1999;5:677–85. - PubMed
    1. Whiteside TL. Immune effector cells in the tumor microenvironment: their role in regulation of tumor progression. In: Yefenof E, editor. Innate and Adaptive Immunity Responses in the Tumor Microenvironment. Springer Science; The Netherlands: 2008. pp. 1–34.
    1. Klebanoff CA, Gattinoni L, Torabi-Parizi P, et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA. 2005;102:9571–76. - PMC - PubMed

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