Until Death Do Us Part: Necrosis and Oxidation Promote the Tumor Microenvironment

Abstract

Tumor proliferation is concomitant with autophagy, limited apoptosis, and resultant necrosis. Necrosis is associated with the release of damage-associated molecular pattern molecules (DAMPs), which act as ‘danger signals', recruiting inflammatory cells, inducing immune responses, and promoting wound healing. Most of the current treatment strategies for cancer (chemotherapy, radiation therapy, hormonal therapy) promote DAMP release following therapy-induced tumor death by necroptosis and necrosis. Myeloid cells (monocytes, dendritic cells (DCs), and granulocytes), as well as mesenchymal stromal cells (MSCs) belong to the early immigrants in response to unscheduled cell death, initiating and modulating the subsequent inflammatory response. Responding to DAMPs, MSCs, and DCs promote an immunosuppressive milieu, while eosinophils induce oxidative conditions limiting the biologic activity of DAMPs over time and distance. Regulatory T cells are strongly affected by pattern recognition receptor signaling in the tumor microenvironment and limit immune reactivity coordinately with myeloid-derived suppressor cells. Means to ‘aerobically' oxidize DAMPs provide a novel strategy for limiting tumor progression. The present article summarizes our current understanding of the impact of necrosis on the tumor microenvironment and the influence of oxidative conditions found within this setting.

Prediction of the efficacy of immunotherapy by measuring the integrity of cell‐free DNA in plasma in colorectal cancer

“…The immunogenic strength of apoptotic or necrotic tumor cells has been reported, controversially, to induce antitumor immunity . In the tumor microenvironment, necrosis or necroptosis has been reported to result in the release of damage‐associated molecular pattern molecules, causing strong immunosuppression through the induction of regulatory T cells, myeloid‐derived suppressor cells and mesenchymal stromal cells . The plasma cfDNA integrity value may be determined from a liquid biopsy to remotely detect the amount of necrosis/necroptosis in tumors and the immunosuppressive microenvironment of the tumor site for predicting the efficacy of immunotherapy with peptide vaccines.…”

“…In general, OS is a preferable endpoint to PFS due to the delayed effect of vaccine therapy . It was speculated that the tumor microenvironment might be altered after chemotherapy due to the large amount of necrosis in the tumor, which results in the release of damage‐associated molecular pattern molecules . Most of the current treatment strategies for cancer (chemotherapy, radiation therapy and hormonal therapy) promote the release of damage‐associated molecular pattern molecules following therapy‐induced tumor death by necroptosis and necrosis.…”

“…(28,29) In the tumor microenvironment, necrosis or necroptosis (30) has been reported to result in the release of damage-associated molecular pattern molecules, causing strong immunosuppression through the induction of regulatory T cells, myeloid-derived suppressor cells and mesenchymal stromal cells. (31) The plasma cfDNA integrity value may be determined from a liquid biopsy to remotely detect the amount of necrosis/ necroptosis in tumors and the immunosuppressive microenvironment of the tumor site for predicting the efficacy of immunotherapy with peptide vaccines. A high cfDNA integrity value may indicate a high degree of tumor collapse and an excess of tumor necrosomes, which promote inducible immune suppression, leading to resistance to immunotherapy and a shorter PFS.…”

“…(13) It was speculated that the tumor microenvironment might be altered after chemotherapy due to the large amount of necrosis in the tumor, which results in the release of damage-associated molecular pattern molecules. (31,32) Most of the current treatment strategies for cancer (chemotherapy, radiation therapy and hormonal therapy) promote the release of damage-associated molecular pattern molecules following therapy-induced tumor death by necroptosis and necrosis. Regulatory T cells are strongly affected by pattern recognition receptor signaling in the tumor microenvironment and they limit immune reactivity in coordination with myeloid-derived suppressor cells.…”

Innate Immune System for Diagnostics and Therapy: Progress in Fundamental Knowledge and Clinical Application

“…DAMPs act as ‘danger signals', recruiting inflammatory cells and promoting chronic inflammation and cancer progression. Lotfi et al [14] suggest that the oxidizing conditions should be considered for therapeutic targeting of the tumour microenvironment, where adoptive transfer of eosinophils or induction of eosinophilia in tumour patients may be helpful. Suck et al [15] elucidated another emerging cell therapy approach which is applied in the treatment of leukaemia and is based on the application of stable engineered NK cell lines.…”