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

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are enzymes which posttranslationally 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.

DNA Damage Response and Immune Defense

“…Accordingly, PARP1 seems to modulate T cells development and the differentiation of peripheral T cells into effector T cells such as T helper 1 (Th1), Th2, and Tregs [ 193 , 194 , 195 ]. As well, recent data showed a role in B cell development; mice with dual, but not individual, PARP-1 and PARP-2 deficiency exhibit a reduced number of B cells in the bone marrow, probably related to unrepaired DNA damage in proliferating B cells and not to an altered Ig V(D)J gene recombination [ 196 ].…”

Dense, high-resolution mapping of cells and tissues from pathology images for the interpretable prediction of molecular phenotypes in cancer

“…In addition, our approach of capturing specific and interpretable features of the tumor and its surroundings can facilitate hypothesis generation and enable a deeper understanding of the TME's influence on drug response. Indeed, recent studies provide evidence that tumor immune architecture can greatly dictate clinical efficacy of immune checkpoint inhibitor 56 and poly (ADP-ribose) polymerase (PARP) inhibitor therapies 57 . Lastly, during both model development and evaluation, we sought to emphasize robustness to real-world variability 58 .…”

Combined PARP Inhibition and Immune Checkpoint Therapy in Solid Tumors

“…This transformation boosts chronic inflammation, immunosuppression, and cancer progression [ 141 , 142 ]. PARPi may have the potential to shift from chronic, low level, DNA damage to more significant T H 1 immune response and create a more susceptible tumor microenvironment [ 143 ]. Nevertheless, the self-sustaining cycle of DNA damage and chronic inflammation, which is challenging to overcome with PARPi single therapeutic approach, could potentially be addressed through combination with ICIs.…”