Over the last 10 years, there’s been a revolution in cancer treatment with immuno-oncology (IO), but responses differ among patients. Better responses are seen in “hot” (immuno-infiltrated) tumours, while “cold” neoplasms don’t respond well to IO. Turning cold tumours into hot could help make them sensitive to IO. This topic was discussed during a dedicated Controversy Session, and a survey was administered to participants before and after the discussion.
- In experimental models, it has already been shown that it is possible to turn cold tumours into hot by inactivating mismatch repair (MMR) genes, leading to an impressive increase in the response to available IO drugs.
- It is not yet possible to translate what is seen in the laboratory to the bedside.
- The majority of the surveyed doctors (93%) think that data are needed on the underlying pathways and immune mechanisms to be able to consistently turn cold tumours into hot.
Why this matters
- The majority of patients still don’t benefit from immunotherapy with checkpoint inhibitors.
Yes. Alberto Bardelli, Candiolo (Turin), Italy
- Somatic mutations (SM) are the key to turning cold tumours into hot.
- Sometimes caused by defects in mechanisms of DNA repair, SM can be recognised by the immune system as “non-self” and trigger cancer surveillance.
- Response to IO is stronger in the presence of a large number of neoantigens derived from SM.
- Acting on MLH1 gene, it was possible to inactivate MMR in colorectal cancers otherwise MMR proficient, increasing the immune (CD4+ and CD8+) infiltration.
- When injected in immunocompetent mice, MMR deficient tumours showed impressive responses to checkpoint inhibitors.
- Inactivation of MMR triggers a dynamic neoantigen evolution which could unlock the immune system to get rid of the tumour.
- Neophore (listed in Dr Bardelli's disclosures) is developing DNA MMR inhibitors that will create neoantigens, increase tumour immunogenicity, and enhance the immunotherapy effect.
No. Thomas Gajewski, Chicago, USA
- In principle, it is possible to turn cold tumours into hot, but we’re not there yet.
- The tumour microenvironment is very complex and some tumours are neither hot nor cold, representing an intermediate “warm” subset.
- A hot tumour is defined by more than just the presence of T cells: specific dendritic populations, chemokines and type I IFN production, and a gene expression profile indicative of local T cell activation also play a role.
- Candidate strategies to convert cold tumours into hot include drugging immune-evasive oncogene pathways, manipulating the gut microbiome and targeting host genetic pathways linked to autoimmunity.
- A successful strategy to expand checkpoint blockade efficacy by transforming cold tumours into hot has yet to be demonstrated.
- We need a better understanding of the basic biology.