It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects.

Persistent STAT5 activation endows antitumor CD4 ⁺ T cells with desirable functional features that optimize adoptive T cell therapy.

Cyclophosphamide (CTX) is a major component of the chemotherapy conditioning regimens used in the clinic to prepare cancer patients for hematopoietic stem cell transplantation or adoptive T cell therapy. Previous studies have shown that CTX given at nonmyeloablative doses in mice and patients leads to expansion of myeloid cells within which the monocytic subset exhibits immunosuppressive activity. However, the ontogeny and gene expression signature of these CTX-induced monocytes are not well-defined. Here, we report that the expansion of myeloid cells is a default process intrinsic to hematopoietic recovery after chemotherapy. During this process, the monocytes repopulated in mice acquire immunosuppressive activity, which can persist long after cessation of chemotherapy. Moreover, monocytes acquire a gene signature characteristic of neutrophil precursors, marked by increased proliferative capability and elevated expressions of multiple primary and secondary granules. We provide evidence that CTX-induced myeloid cell expansion is regulated by DNA methyltransferase 1 (Dnmt1) and dependent on chemotherapy-induced microbial translocation. These findings help advance our understanding of the differentiation, heterogeneity, and function of myeloid cells repopulating after chemotherapy.

The promise and challenges of chimeric antigen receptor T cells in relapsed B-cell acute lymphoblastic leukemia

Cytotoxic chemotherapy primarily targets rapidly proliferating cancer cells but also depletes normal myeloid cells. The resulting cell loss triggers reactive myelopoiesis, a compensatory process in which hematopoietic stem and progenitor cells in the bone marrow (BM) regenerate myeloid lineages. We previously showed that the alkylating agent cyclophosphamide (CTX) induces myelopoiesis, leading to the expansion of immunosuppressive monocytes in mice. However, the molecular features and clinical relevance of these cells remain poorly understood. Here, we report the emergence of immunosuppressive monocytes in the peripheral blood of lymphoma patients receiving CTX-containing chemotherapy. To gain mechanistic insight into CTX-induced myelopoiesis, we performed single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on BM monocytes from CTX-treated mice. These analyses revealed a heterogeneous monocyte population and demonstrated that CTX skews myelopoiesis toward the generation of neutrophil-like monocytes (NeuMo). Moreover, CTX-induced NeuMo cells, enriched within the CXCR4 ⁺ CX3CR1 ^– monocyte subset, exhibited potent T cell–suppressive activity. Using the NeuMo gene signature, reanalysis of public scRNA-seq datasets identified a transcriptionally similar monocyte subset in chemotherapy-treated cancer patients. Collectively, our findings suggest that the expansion of NeuMo cells following chemotherapy represents a conserved immunoregulatory feedback mechanism with potential impact on tumor response to chemoimmunotherapy.