Lung cancer is the main cause of cancer-related deaths worldwide. Surgery is often the preferred treatment for patients with lung cancer; some others are administered chemotherapy and targeted therapy post-surgery(1). While there have been a few advances in lung cancer treatment, the prognosis remains poor. As researchers gain a better understanding of the pathophysiology of lung cancer, several new therapeutic strategies have been proposed, such as immune checkpoint modulation and vaccine therapy(2). Clinical trials show that immunotherapy can afford better overall survival than previous approaches in lung cancer patients(3). Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells, including myeloid progenitor cells, immature granulocytes, immature macrophages, and immature dendritic cells, play a key role in immunosuppression in tumor state(4, 5). Under pathological conditions, such as tumor development, myeloid-derived precursor cells are unable to mature and remain at various stages of differentiation, transforming into MDSCs with immunosuppressive functions(6). MDSCs strongly inhibit the anti-tumor immune response by CD4+ T cells, CD8+ T cells, and natural killer cells in tumor patients, thereby promoting tumor progression(7). Currently, the proposed immunotherapeutic strategies for targeting lung cancer MDSCs include promoting the differentiation of MDSCs, blocking their inhibitory effects, or elimination the cells by using some chemical treatment and antibodies(5, 8). In addition, there is limited research focusing on the origin of MDSCs to nip the increase in their numbers in the bud.
All immune cells in the body, including MDSCs, develop from hematopoietic stem cells (HSCs) in the bone marrow, and HSCs have the ability of long-term self-renewal and the potential to differentiate into various types of mature immune cells. HSCs remain dormant as long-term HSC (LT-HSC), which helps increase the resilience and viability of HSCs(9). In contrast, Wu et al. found that during tumorigenesis (e.g., lung, liver, gastric, and cervical cancers), HSCs are abnormally activated; their ability to self-renew, mobilize, and exhibit homing is altered; and the number of myeloid progenitor cells, GMPs, precursor cells of MDSCs, in peripheral blood is dramatically increased (9–11). The relative abundance of HSCs and GMPs in the peripheral blood of patients with solid tumors has increased dramatically, and their richness is strongly correlated with tumor progression and patient prognosis(11–13). HSCs are located at the top of the immune cell differentiation pyramid, generating numerous functionally distinct monopotent progenitor cells and "terminally differentiated" cells through stepwise differentiation. During this process, the differentiation potential of the cells gradually decreases. However, Faiyaz N. et al. expressed that the differentiation of immune cells was not progressive and their fate may be determined in HSCs, without going through an intermediate differentiation process. Molecules associated with differentiation are already actively expressed in LT-HSCs(14). Naik et al. observed the differentiation of single lymphocyte progenitors (LMPPs) downstream of HSCs and their sister cells and found that all these cells differentiated into dendritic cells, as if they were imprinted with the same "brand"(15). Sanjuan et al. found that thrombo poietin induces HSCs to produce a subpopulation biased towards differentiation into platelets; this subpopulation induces platelet production(16). Therefore, HSCs may respond differently when the environment is subjected to distinctive stimuli, leading to changes in the type of downstream immune cell differentiation, further affecting the development of diseases. In an atherosclerosis mouse model, an abnormally active nervous system reduces CXCL12 expression in the bone marrow, which accelerates HSC proliferation and favors myeloid differentiation, producing more neutrophils and monocytes. These cells, through circulation, reach the nervous system and promote plaque inflammation(17). The hypothesis is that HSCs are not only associated with immune cell development but also participate directly in eliciting immune responses. HSCs, the origin of the immune system, may be aberrantly activated during tumorigenesis and progression, leading to the abnormal differentiation of downstream mature immune cells (e.g., MDSCs), promoting tumor progression.
In recent years, a large number of studies have found that the metabolic reprogramming of HSCs affects their proliferation, survival, and differentiation, and the level of glucose metabolism is closely connected with HSC status(18). Among the many pathways of cellular metabolism, aerobic glycolysis promotes the maintenance of dormant and primed HSCs, and oxidative phosphorylation (OXPHOS) increases significantly with cell differentiation(19). Interrupting or reducing the glycolysis process impairs the stemness of LT-HSCs, leading to the loss of their self-renewal potential(20, 21). Altering the expression of key enzymes of glucose metabolism can affect HSC functions such as dormancy, differentiation, and bone marrow graft reconstruction(22, 23). Pyruvate dehydrogenase kinase (Pdk) is a downstream gene of Hif-α and a key enzyme in the glucose metabolism pathway. Pdk helps HSCs maintain their resting state and apoptotic functions by inhibiting mitochondrial metabolism and the cell cycle. In double knockout Pdk2 and Pdk4 mice, the cell cycle in HSCs was activated and produced fewer erythrocytes. LT-HSCs from Pdk2−/−:Pdk4−/− mice are defective in repopulation after transplantation(24). Tumor suppressor protein kinase (Lkb1) regulates cell proliferation and energy metabolism. Lkb1knockdown induces anemia in mice and causes a decrease in the proportion of myeloid cells(25, 26). On the other hand, alteration of key genes associated with the function of HSCs can also alter their metabolism. Deletion of Cited2, an important gene that regulates the resting and apoptotic functions of HSCs, increased the ROS and mitochondrial activity of HSCs and decreased the expression of the key genes of metabolism, Pdk2 and Pdk4(27). In addition, under pathological conditions, such as aging and tumor development, HSCs change their cellular state to resist extrinsic stimuli through metabolic reprogramming(28–30). Ioannis M. et al. found that β-glucan altered the level of glucose metabolism and cholesterol synthesis in mice, inducing expansion of HSCs and generating more myeloid cells. Immune training of mice using β-glucan allows them to better cope with secondary infections and protects them against chemotherapy-induced bone marrow ablation(31). Thus, we hypothesized that there was an interactive relationship between the function and metabolism of HSCs, and that modulating the metabolism of tumor-HSCs might alter their function and downstream differentiation preferences.
Our study showed that glucose metabolism in HSCs was dramatically altered in the LLC lung cancer mouse model, leading to up-regulation of OXPHOS, elevated mitochondrial number and activity, altered expression of metabolic key enzyme genes, and increased ATP and reactive oxygen species (ROS) levels. In addition, the modulation of glucose metabolic remodeling in HSCs of tumor-bearing mice affected their cell differentiation, with a decrease in the number of MDSCs. Thus, it is possible to influence the type of immune cell differentiation by altering glucose metabolism in HSCs. Our study will improve our understanding of the metabolic change patterns and regulatory mechanisms of HSCs in tumor states and lay the theoretical foundation for tumor immunotherapeutic approaches based on the metabolic intervention of HSCs.