Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death

Abstract

SUMMARY The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal tumors. By conducting metabolic profiling on tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) in tumor cells. We further demonstrate that T cell-derived tumor necrosis factor alpha (TNF-α) can synergize with chemotherapy to intensify oxidative stress and tumor cell death in an NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase-dependent manner. Reduction of oxidative stress, by preventing TNF-α-signaling in tumor cells or scavenging ROS, antagonized the therapeutic effects of adoptive immunotherapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effects of T cell transfer. These findings imply that reinforcing tumor oxidative stress represents an important mechanism underlying the efficacy of adoptive immunotherapy.

The role of reactive oxygen species in tumor treatment

“…The T cell used in ACT can be tumor-inltrating lymphocytes from in vitro expansion; it can also be designed to express tumor-specic antigen T cell receptor (TCR) or a chimeric antigen receptor (CAR). 30 In view of the need for tumor cells to adapt to their high energy demands and uncontrolled growth, tumor therapy targeted at the metabolic pathways required for the survival and growth of tumor cells is also a promising idea. 31 T. Habtetsion and his colleagues altered tumor metabolism through CD4 positive T cells, leading to the increase in the oxidative stress dependent tumor necrosis factor (TNF-) and tumor cell death, as shown in Fig.…”

“…5. 30 Adoptive transfer (AT) of tumor specic CD4 positive T cells pretreated with cytoxan (CTX) was rst proved to produce multifunctional CD4 positive effector cells. These cells produced inammatory cytokines (such as TNF-a, interferon g) and promoted the decay of vessel-intensive tumor.…”

CDK1 and CDC20 overexpression in patients with colorectal cancer are associated with poor prognosis: evidence from integrated bioinformatics analysis

“…Required to maintain individual mitotic chromosomes dispersed in the cytoplasm following nuclear envelope disassembly apoptosis has long been considered as a mechanism for cancer cells to gain a growth advantage over noncancerous cells [19]. Cytokines are involved in regulating immune response, stimulating cell activation, proliferation, and differentiation, and many studies have pointed out that the dysregulation of cytokine, such as TNFα, IL-1β, and IL-22, was associated with the pathological process of CRC [20,21]. Recent researches also pointed out that the cGMP/PKG cascade is recognized as an endogenous apoptotic pathway in numerous cancer types, including CRC [22].…”

Development of a prognostic index and screening of potential biomarkers based on immunogenomic landscape analysis of colorectal cancer

“…Neutrophils also act synergistically with tumor necrosis factor-α (TNFα) to enhance oxidative stress and tumor cell death by. This regimen resulted to curing mice diagnosed with CRC [59]. Other studies have reported that interleukin 22 (IL-22), produced by CD4 (+) T cells in CRC tissues, promote activation of transcription factor STAT3 and the expression of DOT1 Like Histone Lysine Methyltransferase (DOT1L).…”