Cancer cell-autonomous overactivation of PARP1 compromises immunosurveillance in non-small cell lung cancer.

Abstract

BACKGROUND:

High activity of poly(ADP-ribose) polymerase-1 (PARP1) in non-small cell lung cancer (NSCLC) cells leads to an increase in immunohistochemically detectable PAR, correlating with poor prognosis in patients with NSCLC, as well as reduced tumor infiltration by cytotoxic T lymphocytes (CTLs). Intrigued by this observation, we decided to determine whether PARP1 activity in NSCLC cells may cause an alteration of anticancer immunosurveillance.

METHODS:

Continuous culture of mouse NSCLC cells in the presence of cisplatin led to the generation of cisplatin-resistant PARhigh clones. As compared with their parental controls, such PARhigh cells formed tumors that were less infiltrated by CTLs when they were injected into immunocompetent mice, suggesting a causative link between high PARP1 activity and compromised immunosurveillance. To confirm this cause-and-effect relationship, we used CRISPR/Cas9 technology to knock out PARP1 in two PARhigh NSCLC mouse cell lines (Lewis lung cancer [LLC] and tissue culture number one [TC1]), showing that the removal of PARP1 indeed restored cisplatin-induced cell death responses.

RESULTS:

PARP1 knockout (PARP1KO) cells became largely resistant to the PARP inhibitor niraparib, meaning that they exhibited less cell death induction, reduced DNA damage response, attenuated metabolic shifts and no induction of PD-L1 and MHC class-I molecules that may affect their immunogenicity. PARhigh tumors implanted in mice responded to niraparib irrespective of the presence or absence of T lymphocytes, suggesting that cancer cell-autonomous effects of niraparib dominate over its possible immunomodulatory action. While PARhigh NSCLC mouse cell lines proliferated similarly in immunocompetent and T cell-deficient mice, PARP1KO cells were strongly affected by the presence of T cells. PARP1KO LLC tumors grew more quickly in immunodeficient than in immunocompetent mice, and PARP1KO TC1 cells could only form tumors in T cell-deficient mice, not in immunocompetent controls. Importantly, as compared with PARhigh controls, the PARP1KO LLC tumors exhibited signs of T cell activation in the immune infiltrate such as higher inducible costimulator (ICOS) expression and lower PD-1 expression on CTLs.

CONCLUSIONS:

These results prove at the genetic level that PARP1 activity within malignant cells modulates the tumor microenvironment.

• Authors: Pan Juncheng, Adrien Joseph, Antoine Lafarge, Isabelle Martins, Florine Obrist, Jonathan Pol, Ester Saavedra, Sijing Li, Allan Sauvat, Giulia Cerrato, Sarah Lévesque, Marion Leduc, Oliver Kepp, Sylvère Durand, Fanny Aprahamian, Nitharsshini Nirmalathansan, Judith Michels, Guido Kroemer, Maria Castedo
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 10 Issue 6 (06 2022) ISSN: 2051-1426 [Electronic] England
• PMID: 35772809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Poly(ADP-ribose) Polymerase Inhibitors
• Cisplatin

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Cisplatin (pharmacology, therapeutic use)
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Mice
• Monitoring, Immunologic
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology, therapeutic use)
• Tumor Microenvironment