Increased inflammatory signature in myeloid cells of non-small cell lung cancer patients with high clonal hematopoiesis burden

Reviewer #1 (Public Review):

Summary:

The study investigates the impact of Clonal Hematopoiesis of Indeterminate Potential (CHIP) on Immune Checkpoint Inhibitor (ICI) therapy outcomes in NSCLC patients, analyzing blood samples from 100 patients pre- and post-ICI therapy for CHIP, and conducting single-cell RNA sequencing (scRNA-seq) of PBMCs in 63 samples, with validation in 180 more patients through whole exome sequencing. Findings show no significant CHIP influence on ICI response, but a higher CHIP prevalence in NSCLC compared to controls, and a notable CHIP burden in squamous cell carcinoma. Severely affected CHIP groups showed NF-kB pathway gene enrichment in myeloid clusters.

Strengths:

The study is commendable for analyzing a significant cohort of 100 patients for CHIP and utilizing scRNA-seq on 63 samples, showcasing the use of cutting-edge technology.

The study tackles the vital clinical question of predicting ICI therapy outcomes in NSCLC.

Weaknesses:

The manuscript's comparison of CHIP prevalence between NSCLC patients and healthy controls could be strengthened by providing more detailed information on the control group. Specifically, details such as sex, smoking status, and comorbidities are needed to ensure the differences in CHIP are attributable to lung cancer rather than other factors. Including these details, along with a comparative analysis of demographics and comorbidities between both groups and clarifying how the control group was selected, would enhance the study's credibility and conclusions.

Reviewer #2 (Public Review):

Summary:

The authors used a large cohort of patients with metastatic lung cancer pre- and 1-3 weeks post-immunotherapy. The goal was to investigate whether immunotherapy results in changes in CHIP clones (using targeted sequencing and whole exome sequencing) as well as to investigate whether patients with CHIP changed their response to immunotherapy (single-cell RNA sequencing).

Strengths:

This represents a large cohort of patients, and comprehensive assays - including targeted sequencing, whole exome sequencing, and single-cell RNA sequencing.

Weaknesses:

Findings are not necessarily unexpected. With regards to clonal dynamics, it would be very unlikely to see any changes within a few weeks' time frame. Longer follow-up to assess clonal dynamics would realistically be necessary.