There is no doubt that obesity will eventually become the first avoidable risk factor for cancer, before tobacco. Nonetheless, the molecular comprehension of this epidemiological link is in its infancy, requiring in-depth investigation in several major cancers (in particular, breast, colorectal and hepatocellular cancer). For instance, it will be important to understand which genetically or immunologically defined subtypes of cancer are associated with particular metabolic aberrations. Although it has been generally assumed that major aberrations in metabolism (due to caloric excess, poor quality of nutrition, ingestion of toxins, alterations of the gut microbiota, absence of physical activity etc.) may cause oncogenesis and tumor progression via cell-autonomous effects, it has become increasingly clear that metabolic alterations may impact on cancer via indirect, leukocyte-dependent effects, namely, chronic, pro-carcinogenic inflammation as well as reduced anticancer immunosurveillance [Zitvogel Nature Immunology 2017].

The discovery of metabolic aberrations within cancers may yield new actionable targets in the area of immuno-oncology. For example, autophagy, which has major roles in metabolism [Galluzzi Cell 2014] can be targeted for tumor therapy [Galluzzi EMBO J 2016]. Suppressed autophagy is a general feature of obesity and old age [Lopez-Otin Cell 2016]. CARPEM-associated teams have demonstrated that autophagy-deficient mouse cancers fail to elicit an anticancer immune response in the context of chemotherapy or radiotherapy [Michaud Science 2011, Galluzzi Nat Rev Clin Oncol 2017] and that, in human breast cancers, treated with adjuvant chemotherapy, defective autophagy is associated with poor immunosurveillance, as indicated by a poor CD8/FOXP3 ratio [Kroemer Nature Med 2015, Ladoire Autophagy 2016]. Hence strategies may be developed to induce autophagy by fasting or novel pharmacological agents [Galluzzi Nat Rev Drug Discov 2017] with the scope of stimulating the anticancer immune response [Pietrocola Cancer Cell 2016]. In contrast, in colorectal cancer autophagy inhibition might be envisaged to prevent onocogenesis [Levy Nat Cell Biol 2015].

The CARPEM consortium also discovered that pyridoxine (vitamin B6) can stimulate anticancer immune responses in the context of cisplatin-treated orthotopic mouse non-small cell lung cancers (NSCLC) [Aranda Oncogene 2015]. In human NSCLC, low levels of pyridoxal kinase (PDXK) expression by neoplastic cells correlates with a weak infiltration by DC-LAMP+ dendritic cells (DC) and indicates poor prognosis [Galluzzi Cell Report 2012].  Moreover, high levels of poly adenosine ribosyl (PAR) adducts produced by PAR polymerase-1 (PARP) correlate with weak infiltration by CD8+ cytotoxic T lymphocytes (CTL) in human NSCLC, and both elevated PAR levels and low infiltration by CTL indicate poor prognosis [Michels et al. 2014 Cancer Research; Michels et al. 2016 Annals Oncology; Fridman Nat Rev Clin Oncol 2017]. This suggests the possibility to use PARP inhibitors as immunomodulators in specific circumstances.

CARPEM will continue these lines of investigation with the quadruple objective to:

• establish new, more precise associations between metabolic features and molecular/immunological cancer subtypes,
• investigate new cause-effect relationships between dysmetabolism and oncogenesis, tumor progression,  failure of immunosurveillance and therapy resistance,
• establish novel biomarkers for risk stratification in major cancer types, and
• identify molecular targets that may constitute intervention points for the clinical and pharmacological management of cancer patients.