2MO - Tracking immunoediting from early to late stage lung cancer

Background

Tumour cells acquire somatic mutations during cancer evolution, some of which result in neoantigens, novel peptides that elicit an immune response. As tumour cells bearing neoantigens are more likely to be eliminated by immune cells, tumours within T cell-rich environments might be expected to have ‘immunoedited’ tumour mutational landscapes characterised by neoantigen depletion. Although reduced neoantigen burden is associated with poor response to immunotherapy and survival in multiple cancer types, studies that have aimed to measure immunoediting signals from DNA sequencing data have obtained contrasting results. We hypothesise that these differences might relate to variation in immunoediting at distinct tumour evolutionary stages. Therefore, we investigated the immunoediting timelines of primary and metastatic tumour clones by mapping immunoediting signals to their phylogenetic trees.

Methods

Tumour phylogenies were reconstructed using somatic mutations identified from whole exome sequencing data obtained from 18 multi-region sampled primary tumours and 300 paired metastases from patients with non-small cell lung cancer co-recruited to the national TRACERx study and PEACE autopsy programme. We predicted the neoantigen status of all mutations and measured signals of immunoediting using four existing computational methods.

Results

We created a simulation framework based on TRACERx and PEACE sequencing data to establish the reliability of existing methods that measure immunoediting. Using this framework, we developed a new approach to quantify immunoediting that combines the best performing features of existing methods. We applied this method to primary and metastatic tumour clones which revealed that distinct phylogenetic branches have distinct immunoediting signals. Investigating these differences, we identified examples of immunoediting cessation following subclonal disruption of antigen presentation.

Conclusions

In summary, these findings suggest that immune selective pressures are dynamic from early to late stage disease and, as such, signals of immunoediting should be interpreted within the context of a tumour’s evolutionary history.

Clinical trial identification

TRACERx study: NCT01888601; PEACE study: NCT03004755.

Legal entity responsible for the study

The authors.

Funding

Cancer Research UK, Rosetrees Trust.

Disclosure

D. Moore: Financial Interests, Personal, Invited Speaker: AstraZeneca, Takeda; Financial Interests, Personal, Advisory Role: Thermo Fisher, Amgen, Janssen, Eli Lilly. N. McGranahan: Financial Interests, Institutional, Stocks/Shares: Achilles Therapeutics. C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GlaxoSmithKline; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board: Genentech, Sarah Canon Research Institute, Medicxi; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Science Management Committee. Also have stock options: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, ApoGen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies: Archer Dx Inc.; Financial Interests, Institutional, Research Grant: Pfizer, Ono Pharmaceutical, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD1 clinical trial and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research Grants from 2015-2019: Roche-Ventana; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD1 clinical trial: AstraZeneca; Non-Financial Interests, Personal, Invited Speaker, From 2019: AACR; Non-Financial Interests, Personal, Other, Board of Directors: AACR; Non-Financial Interests, Personal, Advisory Role, EACR Advisory Council member: EACR. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited Speaker Honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, Personal, Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection: Patent. All other authors have declared no conflicts of interest.