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Abstract
Background Clonal hematopoiesis (CH) is characterized by clonal expansion of hematopoietic stem cells harboring somatic driver mutations for hematologic malignancies in epigenetic regulator genes such as the DNMT3A, TET2, and ASXL1.1 CH is a hallmark of aging and has been linked with age-associated diseases, possibly due to CH-induced proinflammatory immune phenotypes.2 Despite growing evidence of the role of CH in altered inflammatory signaling, little is known about its role in anti-tumor immune-modulatory treatment such as immune checkpoint inhibitors (ICIs).
Methods To investigate the effect of CH on ICI response, we leveraged blood-derived whole-exome sequencing of 1,456 anti-PDL1 (as monotherapy or combination with chemotherapy) treated patients from five non-small cell lung cancer clinical trials (FIR, POPLAR, IMpower110, IMpower150, IMpower131) and one small cell lung cancer trial (IMpower133). We performed somatic variant calling using Mutect2,3 and annotated individuals who carried at least one known driver mutation from 43 CH-related genes detailed in Kar et al 4 as CH carriers.
Results Among the study participants, 14.1% were categorized as CH carriers (table 1). Consistent with previous reports, we observed no CH among the younger patients (<40 years) (figure 1A), and a substantially increased prevalence in older patients (>35% in patients >80 years). To investigate the relevance of CH in ICI response (complete/partial response vs. progressive/stable disease), we performed multivariable logistic regression adjusted for age, sex, and smoking history. The meta-analysis in the anti-PDL1 cohort indicated that CH carriers were more likely to experience reduced response compared to non-carriers (OR=1.71 [1.12–2.61]; p-value=0.01) (figure 1B). A consistent result was noted when considering only the NSCLC subset of studies (OR=1.69 [1.08–2.62]; p-value=0.02). We did not observe the same association in the control arms of the trials (OR=0.77 [0.40–1.48]; p-value=0.43) (figure 1B), suggesting that the unfavorable effect of CH is unique to ICI.
Conclusions Our study reported an adverse impact of CH on ICI response, revealing its potential role as a novel biomarker. Loss of common CH-driver genes such as DNMT3A has been linked with enhanced expression of immune-suppressive cytokines (e.g., IL6).2 which were previously found to attenuate ICI response.5 6 Additionally, previous evidence implicates a direct tumor-focused impact in the tumor microenvironment,7 which may also contribute to the results of our study. While functional experiments are warranted to further elucidate the mechanism of action, our investigation provides an intriguing observation that CH may play an important role in modulating the anti-tumor immune response in ICI-treated patients.
References
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Ethics Approval ’Patients included in this study signed an informed consent form (ICF), providing informed consent for analysis of inherited and non-inherited genetic variation from whole blood samples. Ethics Committees (EC) and Institutional Review Boards (IRB) in each country and each study site for each clinical trial approved the clinical trial protocol and ICF.’
Consent ’Patients included in this study signed an informed consent form (ICF), providing informed consent for analysis of inherited and non-inherited genetic variation from whole blood samples. Ethics Committees (EC) and Institutional Review Boards (IRB) in each country and each study site for each clinical trial approved the clinical trial protocol and ICF.’
Characteristics of the study cohort
(A) Distribution of CHIP prevalence by age groups. (B) Forest plot of the association of CHIP with anti-PDL1 treatment response in the anti-PDL1 (top) and control (bottom) cohorts
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