Metabolic features of cancer cells impact immunosurveillance

Adrien Joseph; Pan Juncheng; Michele Mondini; Nizar Labaied; Mauro Loi; Julien Adam; Antoine Lafarge; Valentina Astesana; Florine Obrist; Christophe Klein; Norma Bloy; Gautier Stoll; Nicolas Signolle; Catherine Genestie; Diane Damotte; Marco Alifano; Alexandra Leary; Patricia Pautier; Philippe Morice; Sebastien Gouy; Eric Deutsch; Cyrus Chargari; Marie-Caroline Dieu-Nosjean; Isabelle Cremer; Judith Michels; Guido Kroemer; Maria Castedo

doi:10.1136/jitc-2021-002362

Metabolic features of cancer cells impact immunosurveillance

J Immunother Cancer. 2021 Jun;9(6):e002362. doi: 10.1136/jitc-2021-002362.

Authors

Adrien Joseph^{1

2

3}, Pan Juncheng^{1

2

3}, Michele Mondini⁴, Nizar Labaied⁵, Mauro Loi⁶, Julien Adam^{7

8}, Antoine Lafarge^{1

2

3}, Valentina Astesana^{1

2

3}, Florine Obrist^{1

2

3}, Christophe Klein⁹, Norma Bloy^{1

2

3}, Gautier Stoll^{1

2}, Nicolas Signolle⁵, Catherine Genestie⁵, Diane Damotte¹⁰, Marco Alifano¹¹, Alexandra Leary¹², Patricia Pautier¹², Philippe Morice¹³, Sebastien Gouy¹³, Eric Deutsch¹⁴, Cyrus Chargari¹⁴, Marie-Caroline Dieu-Nosjean¹⁵, Isabelle Cremer¹⁶, Judith Michels¹⁷, Guido Kroemer^{18

19

20

21}, Maria Castedo^{18

2}

Affiliations

¹ Equipe 11 labellisée par la Ligue contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, INSERM, Paris, France.
² Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
³ Faculté de médecine, Université de Paris Saclay, Kremlin Bicêtre, France.
⁴ INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
⁵ Pathology Department, Gustave Roussy Institute, Villejuif, Île-de-France, France.
⁶ INSERM U1030, Gustave Roussy, Université Paris-Saclay, INSERM, Villejuif, Val-de-Marne, France.
⁷ Pathology Department, Gustave Roussy Institute, Villejuif, Val-de-Marne, France.
⁸ Pathology Department, Gustave Roussy Cancer Campus, Villejuif, France.
⁹ Centre d'Histologie, Imagerie cellulaire et Cytométrie (CHIC), Centre de Recherche des Cordeliers, Paris, Île-de-France, France.
¹⁰ Departments of Pathology and Thoracic Surgery, Hospital Cochin Assistance Publique Hopitaux de Paris, APHP, Paris, Île-de-France, France.
¹¹ Department of Thoracic Surgery, Hospital Cochin Assistance Publique Hopitaux de Paris, APHP, Paris, Île-de-France, France.
¹² Department of Medical Oncology, Gustave Roussy Institute, Villejuif, Île-de-France, France.
¹³ Department of Gynecologic Surgery, Gustave Roussy Institute, Villejuif, Île-de-France, France.
¹⁴ Radiotherapy Department, Brachytherapy Unit, Gustave Roussy Institute, Villejuif, Val-de-Marne, France.
¹⁵ Sorbonne University, UMRS 1135, INSERM U1135, Centre d'Immunologie et des Maladies Infectieuses (Cimi-Paris), INSERM, Paris, Île-de-France, France.
¹⁶ INSERM U1138, Centre de Recherche des Cordeliers, Université de Paris, Sorbonne Université, 75006 Paris, France.
¹⁷ Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France maria.castedo-delrieu@sorbonne-universite.fr kroemer@orange.fr michelsjudith@gmail.com.
¹⁸ Equipe 11 labellisée par la Ligue contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, INSERM, Paris, France maria.castedo-delrieu@sorbonne-universite.fr kroemer@orange.fr michelsjudith@gmail.com.
¹⁹ Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
²⁰ Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
²¹ Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.

Abstract

Background: Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types.

Methods: Tumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PAR^low) and cisplatin-resistant (PAR^high) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry.

Results: The infiltration of tumors by CD8 T and DC-LAMP⁺ cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p<0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=-0.39, p=0.034 in LACC, R=-0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR^high). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086).

Conclusions: Oncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure.

Keywords: CD8-positive t-lymphocytes; dendritic cells; immunotherapy; lung neoplasms; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Female
Humans
Immunotherapy / methods*
Mice
Monitoring, Immunologic / methods*
Neoplasms / immunology*
Tumor Microenvironment / immunology