8O - Clinical implications of clonal hematopoiesis in the tumor microenvironment of non-small cell lung cancer

Background

Clonal hematopoiesis of indeterminate potential (CHIP) represents the expansion of hematopoietic stem cells that have acquired mutations in genes associated with myeloid malignancies. CHIP confers a risk for cardiovascular diseases, haematological malignancies and death from solid tumours, including non-small cell lung cancer (NSCLC). However, the clinical impact of CHIP-mutated immune cells infiltrating the tumour microenvironment (TME) is not well characterized.

Methods

We studied 421 patients with NSCLC as part of the TRACERx study. CHIP mutations were extracted from exome sequencing data (median 400X) of the patients’ blood. The CHIP mutations were then genotyped in 1,770 surgical tumour regions. The cellular compositions of the TME were estimated using imaging mass cytometry and RNA sequencing data. Time-to-event endpoints analysis was performed using Cox proportional hazards regression. Findings were validated on TCGA data from 727 patients with NSCLC.

Results

CHIP was observed in 33% (140 of 421) of TRACERx patients, of which 46% (64 of 140) had CHIP-mutated immune cells infiltrating the TME (i.e., tumor infiltrating CHIP, or t-CHIP). t-CHIP was associated with a skew towards myeloid cells (neutrophils, monocytes) in the TME (log2 fold-change=1.6, pval=0.001). An increased expression of CXCL8, a known marker of inflammation, was observed in t-CHIP tumor regions. t-CHIP was also found to persist in primary-matched metastatic samples. Although CHIP was associated with an increased risk of disease recurrence or death in a multivariable model (HR=1.4, 95% CI 1.1-1.9), t-CHIP specifically, and not CHIP alone, was an independent predictor of adverse outcomes (HR=2.0, 95% CI 1.1-3.6).

Conclusions

The infiltration of the TME by CHIP was pervasive in primary and metastatic samples, and adversely affected patient outcome in NSCLC.

Editorial acknowledgement

Clinical trial identification

NCT01888601.

Legal entity responsible for the study

The authors.

Funding

CRUK, UKRI.

Disclosure

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, GSK; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; 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, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Personal, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Personal, Other, Board of Directors: AACR; Non-Financial Interests, Personal, Advisory Role, EACR Advisory Council member: EACR. All other authors have declared no conflicts of interest.