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. 2024 Oct 15;25(20):11049.
doi: 10.3390/ijms252011049.

Immune Checkpoint Inhibitor Therapy and Associations with Clonal Hematopoiesis

Abhay Singh  1 , Nuria Mencia Trinchant  2 , Rahul Mishra  3 , Kirti Arora  4 , Smit Mehta  1 , Teodora Kuzmanovic  1 , Maedeh Zokaei Nikoo  5 , Inderpreet Singh  6 , Amanda C Przespolewski  7 , Mahesh Swaminathan  7 , Marc S Ernstoff  7 , Grace K Dy  7 , Lunbiao Yan  2 , Eti Sinha  2 , Shruti Sharma  6 , Duane C Hassane  2   8 , Elizabeth A Griffiths  7 , Eunice Wang  7 , Monica L Guzman  2 , Swapna Thota  9
Affiliations

Immune Checkpoint Inhibitor Therapy and Associations with Clonal Hematopoiesis

Abhay Singh et al. Int J Mol Sci. .

Abstract

Cancer cohorts are now known to be associated with increased rates of clonal hematopoiesis (CH). We sort to characterize the hematopoietic compartment of patients with melanoma and non-small cell lung cancer (NSCLC) given our recent population level analysis reporting evolving rates of secondary leukemias. The advent of immune checkpoint blockade (ICB) has dramatically changed our understanding of cancer biology and has altered the standards of care for patients. However, the impact of ICB on hematopoietic myeloid clonal expansion remains to be determined. We studied if exposure to ICB therapy affects hematopoietic clonal architecture and if their evolution contributed to altered hematopoiesis. Blood samples from patients with melanoma and NSCLC (n = 142) demonstrated a high prevalence of CH. Serial samples (or post ICB exposure samples; n = 25) were evaluated in melanoma and NSCLC patients. Error-corrected sequencing of a targeted panel of genes recurrently mutated in CH was performed on peripheral blood genomic DNA. In serial sample analysis, we observed that mutations in DNMT3A and TET2 increased in size with longer ICB exposures in the melanoma cohort. We also noted that patients with larger size DNMT3A mutations with further post ICB clone size expansion had longer durations of ICB exposure. All serial samples in this cohort showed a statistically significant change in VAF from baseline. In the serial sample analysis of NSCLC patients, we observed similar epigenetic expansion, although not statistically significant. Our study generates a hypothesis for two important questions: (a) Can DNMT3A or TET2 CH serve as predictors of a response to ICB therapy and serve as a novel biomarker of response to ICB therapy? (b) As ICB-exposed patients continue to live longer, the myeloid clonal expansion may portend an increased risk for subsequent myeloid malignancy development. Until now, the selective pressure of ICB/T-cell activating therapies on hematopoietic stem cells were less known and we report preliminary evidence of clonal expansion in epigenetic modifier genes (also referred to as inflammatory CH genes).

Keywords: DNMT3A; TET2; clonal hematopoiesis of indeterminate potential; immune checkpoint blockade; immune checkpoint inhibitor; melanoma; non-small cell lung cancer.

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Conflict of interest statement

Dr. Duane C. Hassane was employed at Tempus Labs, Inc. The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
(A) Description of clinical, hematological, and genetic characteristics of patients with melanoma. (B) Description of clinical, hematological, and genetic characteristics of patients with non-small cell lung cancer. ANC (absolute neutrophil count); Hgb (hemoglobin); MCV (mean corpuscular volume, fL); RDW (red cell distribution width, %); CV (cardiovascular disease); DVT/PE (Deep vein thrombosis/Pulmonary embolism); AID (Autoimmune disease); IrAE (Immune-related adverse events). Race (AA: African American; O: other; W: White), SCC: Squamous cell cancer; NOS (Not otherwise specified); CVD/PAD (cardiovascular disease/Peripheral arterial disease).
Figure 2
Figure 2
(a) Change in clonal architecture in serial blood samples after exposure to immune checkpoint inhibitor (ICB) in five patients with melanoma. Spider plot depicts difference in variant allele frequencies (VAF) (y-axis) in blood samples pre- and post-ICB therapy ICB (Immune checkpoint inhibitor) plotted against time between pre- and post-sample collection (x-axis); Pre-ICB sample collection at day 0. (b) Age, hematological and treatment characteristics in patients with melanoma and clonal hematopoiesis mutations, at baseline. ANC (absolute neutrophil count, 103/µL); Hgb (hemoglobin, gm/dL); MCV (mean corpuscular volume, fL); RDW (red cell distribution width, %); VAF (Variant allele frequency).
Figure 2
Figure 2
(a) Change in clonal architecture in serial blood samples after exposure to immune checkpoint inhibitor (ICB) in five patients with melanoma. Spider plot depicts difference in variant allele frequencies (VAF) (y-axis) in blood samples pre- and post-ICB therapy ICB (Immune checkpoint inhibitor) plotted against time between pre- and post-sample collection (x-axis); Pre-ICB sample collection at day 0. (b) Age, hematological and treatment characteristics in patients with melanoma and clonal hematopoiesis mutations, at baseline. ANC (absolute neutrophil count, 103/µL); Hgb (hemoglobin, gm/dL); MCV (mean corpuscular volume, fL); RDW (red cell distribution width, %); VAF (Variant allele frequency).
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