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Review
. 2020 Feb 8;12(2):392.
doi: 10.3390/cancers12020392.

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

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Free PMC article
Review

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

José Yélamos et al. Cancers (Basel). .
Free PMC article

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are enzymes which post-translationally modify proteins through poly(ADP-ribosyl)ation (PARylation)-the transfer of ADP-ribose chains onto amino acid residues-with a resultant modulation of protein function. Many targets of PARP-1/2-dependent PARylation are involved in the DNA damage response and hence, the loss of these proteins disrupts a wide range of biological processes, from DNA repair and epigenetics to telomere and centromere regulation. The central role of these PARPs in DNA metabolism in cancer cells has led to the development of PARP inhibitors as new cancer therapeutics, both as adjuvant treatment potentiating chemo-, radio-, and immuno-therapies and as monotherapy exploiting cancer-specific defects in DNA repair. However, a cancer is not just made up of cancer cells and the tumor microenvironment also includes multiple other cell types, particularly stromal and immune cells. Interactions between these cells-cancerous and non-cancerous-are known to either favor or limit tumorigenesis. In recent years, an important role of PARP-1 and PARP-2 has been demonstrated in different aspects of the immune response, modulating both the innate and adaptive immune system. It is now emerging that PARP-1 and PARP-2 may not only impact cancer cell biology, but also modulate the anti-tumor immune response. Understanding the immunomodulatory roles of PARP-1 and PARP-2 may provide invaluable clues to the rational development of more selective PARP-centered therapies which target both the cancer and its microenvironment.

Keywords: PARP; immunomodulation; tumor microenvironment.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic representation of T cell development depicting the specific stages in which PARP-1 and/or PARP-2 are playing a role. TCR, T cell receptor; DN, double negative; DP, double positive; SP, single positive; DC, dendritic cells; Treg, regulatory T cells.
Figure 2
Figure 2
Schematic representation of B cell development depicting the specific stages in which PARP-1 and/or PARP-2 play a role. MZ, marginal zone; FO, follicular B cells; TD, T cell-dependent antigen; TI, T cell-independent antigen; SHM, somatic hypermutation.
Figure 3
Figure 3
Schematic representation of the role played by PARP-1 in cells of the innate immune system.
Figure 4
Figure 4
Schematic representation of the tumor microenvironment indicating the stages in which PARP-1 or its combination with PARP-2 or PARP inhibitors might play a role. In the boxes, we have included further details on the involvement of PARP-1 and/or PARP-2 or PARPi in certain contexts of the immune response. CTL, cytotoxic T cells; DC, dendritic cells; B, B cells; PARPi, PARP inhibitors.

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