Abstract Background and Objective: Clonal hematopoiesis (CH) arises from expansion of hematopoietic stem cells bearing somatic mutations, and is associated with increased all-cause mortality, hematologic malignancy, and cardiovascular disease. Epidemiologic studies show that CH is more prevalent in individuals with solid tumors, but whether CH influences solid tumor pathogenesis remains poorly understood. Recent reports in non-small cell lung cancer (NSCLC) suggest that mutant hematopoietic cells infiltrate the tumor microenvironment and are associated with inferior outcomes, but causality has not been established. We report the first congenic, autochthonous mouse model, to study the relationship between TET2-mutant CH and lung adenocarcinoma (LUAD) development driven by inducible KrasG12D activation and p53 loss. Using this model, we found that the presence of TET2-mutant CH altered the immune composition of both normal lung parenchyma and the tumor microenvironment but did not change the pathogenesis or growth of LUAD. These data suggest that additional efforts to incorporate a wider range of human samples, animal models, and integration of treatments are required to define the relationship between CH and lung cancer phenotypes. Methods: IrradiatedKrasLSL-G12D/+;Trp53fl/fl (KP) mice were reconstituted with bone marrow from Tet2fl/fl;Vav-Cre (Tet2 KO) or control (Tet2 WT) donors to generate mice with wild-type or Tet2-mutant hematopoiesis. After hematopoietic reconstitution, LUAD was induced by intratracheal Adeno-Cre. Peripheral blood and spleen immune composition were assessed by flow cytometry. Lung tumor burden was followed by CT imaging and quantified by histopathology at 12- and 16-weeks post-induction. Immune infiltrates and tertiary lymphoid structures (TLS) in lungs and tumors were evaluated by flow cytometry and immunohistochemistry, respectively. Results: Eight weeks post-transplantation, Tet2 KO recipients demonstrated multiple differences in the peripheral blood compared to Tet2 WT recipients including expansion of T cells, monocytes, and neutrophils with a concomitant decrease in B cells. Differences in the spleen included enrichment of CD4+ T cells and conventional dendritic cells with skewing toward cDC2 over cDC1 in the Tet2 KO mice. Despite these alterations, we observed no difference in tumor burden or histologic grade between Tet2 KO and WT mice at either 12 or 16 weeks after induction of LUAD. However, profound immunologic remodeling was observed in lungs of Tet2 KO mice. For example, independent of tumor presence, Tet2 KO mice exhibited a higher frequency of tertiary lymphoid structures (TLS) in normal lung parenchyma, with genotype-dependent variation in their composition: Tet2 KO TLS harbored more CD4+ and fewer CD8+ and Foxp3+ T cells, more macrophages, and fewer Ly6G+ myeloid cells. Within tumors, the immune microenvironment of Tet2 KO mice was similarly characterized by an increased CD4/CD8 ratio and higher macrophage content, with a non-significant trend toward more Ly6G+ and B cells. Conclusions: Tet2-mutant hematopoiesis in this congenic, autochthonous KP model profoundly reshapes systemic and tissue-resident immunity, including the composition of TLS in the lung and the tumor microenvironment of LUAD, but does not alter tumor burden or tumor grade. These findings support clinical observations that CH modifies immune cell behavior in solid tumors but suggest that, in the absence of therapy, TET2 mutations may not directly enhance LUAD progression. The study highlights the complexity of CH–solid tumor interactions and suggests that effects on tumor pathogenesis may depend on tumor immunogenicity, model context, and therapeutic pressures. Future studies incorporating additional CH mutations, tumor models, and therapeutic interventions are warranted.
Parisi et al. (Mon,) studied this question.