Cancer cell-autonomous overactivation of PARP1 compromises immunosurveillance in non-small cell lung cancer - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal for Immunotherapy of Cancer Année : 2022

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

Pan Juncheng
Adrien Joseph
Antoine Lafarge
  • Fonction : Auteur
Isabelle Martins
  • Fonction : Auteur
Florine Obrist
  • Fonction : Auteur
Ester Saavedra
  • Fonction : Auteur
Sijing Li
  • Fonction : Auteur
Sarah Lévesque
  • Fonction : Auteur
Marion Leduc
  • Fonction : Auteur
Oliver Kepp
  • Fonction : Auteur
Fanny Aprahamian
  • Fonction : Auteur
Nitharsshini Nirmalathansan
  • Fonction : Auteur
Judith Michels
  • Fonction : Auteur
Guido Kroemer
Maria Castedo

Résumé

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 PAR high clones. As compared with their parental controls, such PAR high 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 PAR high 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 (PARP1 KO ) 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. PAR high 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 PAR high NSCLC mouse cell lines proliferated similarly in immunocompetent and T cell-deficient mice, PARP1 KO cells were strongly affected by the presence of T cells. PARP1 KO LLC tumors grew more quickly in immunodeficient than in immunocompetent mice, and PARP1 KO TC1 cells could only form tumors in T cell-deficient mice, not in immunocompetent controls. Importantly, as compared with PAR high controls, the PARP1 KO 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.
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Dates et versions

hal-04596634 , version 1 (31-05-2024)

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Pan Juncheng, Adrien Joseph, Antoine Lafarge, Isabelle Martins, Florine Obrist, et al.. Cancer cell-autonomous overactivation of PARP1 compromises immunosurveillance in non-small cell lung cancer. Journal for Immunotherapy of Cancer, 2022, 10 (6), pp.e004280. ⟨10.1136/jitc-2021-004280⟩. ⟨hal-04596634⟩
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