Antitumor Activity Of Tumor Necrosis Factor Research Articles

"Designer cytokines" targeting the tumor vasculature-think global and act local.

Tumor necrosis factor (TNF) was discovered in 1975 as a lipopolysaccharide-induced serum factor that causes necrosis of tumors (Carswell etal, 1975). It was later found that TNF and cachectin, a factor causing wasting disease, were one and the same molecule (Beutler etal, 1985). Studies on the inflammatory activity of TNF have been translated into clinical success, namely blocking antibodies used to suppress autoimmune diseases. Research on TNF anti-tumor activity, in contrast, has not yet resulted in a therapeutic breakthrough. This may change, based on a study by Huyghe etal (2020) describing novel "designer cytokines" (TNFand interferon-γ) that increase local activity by targeting the CD13-positive tumor vasculature, while simultaneously lowering the binding affinity to the respective cytokine receptor, thereby reducing off-target effects on normal cells.

Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

New opportunities are needed to increase immune checkpoint blockade (ICB) benefit. Whereas the interferon (IFN)γ pathway harbors both ICB resistance factors and therapeutic opportunities, thishas not been systematically investigated for IFNγ-independent signaling routes. A genome-wide CRISPR/Cas9 screen to sensitize IFNγ receptor-deficient tumor cells to CD8 Tcell elimination uncovered several hits mapping to the tumor necrosis factor (TNF) pathway. Clinically, we show that TNF antitumor activity is only limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Taking advantage of the genetic screen, we demonstrate that ablation of the top hit, TRAF2, lowers the TNF cytotoxicity threshold in tumors by redirecting TNF signaling to favor RIPK1-dependent apoptosis. TRAF2 loss greatly enhanced the therapeutic potential of pharmacologic inhibition of itsinteraction partner cIAP, another screen hit, thereby cooperating with ICB. Our results suggest that selective reduction of the TNF cytotoxicity threshold increases the susceptibility of tumors to immunotherapy.

Protection against TNF-Induced Lethal Shock by Soluble Guanylate Cyclase Inhibition Requires Functional Inducible Nitric Oxide Synthase

Hypotension and shock observed in sepsis, SIRS, and tumor necrosis factor (TNF) or cytokine-based cancer treatment are the consequence of excessive nitric oxide (NO) production and subsequent soluble guanylate cyclase (sGC)-mediated vascular smooth muscle relaxation. We demonstrate here that, while NO synthase (NOS) inhibitors exacerbated toxicity, inhibitors of sGC activation protected against TNF-induced lethality, bradycardia, and hypotension. Importantly, sGC inhibition did not interfere with the antitumor activity of TNF. Using NOS inhibitors or iNOS-deficient animals, we furthermore observed that no protection against TNF toxicity could be obtained in the absence of NO. These data imply that iNOS- (and not eNOS-) derived NO is an endogenous protective molecule indispensable to survive a TNF challenge and exerting this beneficial effect via sGC-independent mechanisms.

Anti-tumor activity of tumor necrosis factor in combination with interferon-gamma is not affected by prior tolerization.

Repetitive administration of low doses of tumor necrosis factor (TNF) results in a state of selective tolerance to some of its effects. We have demonstrated that tolerance does not impair the therapeutic efficacy of TNF against a syngeneic murine B16BL6 melanoma and allows a complete cure. Another study, performed with a distinct tumor model, came to apparently contradictory results. To clarify this, we investigated whether the outcome depended on the tumor type and on the inclusion of interferon-gamma (IFN gamma) in the treatment. Three syngeneic tumors of different histological origin, i.e., B16BL6 melanoma, Lewis lung carcinoma (LLC) and EL4 lymphoma, were compared in C57BL/6 mice. The anti-tumor efficacy of TNF against B16BL6 and EL4 was not impaired in tolerant mice, but the effect of TNF against LLC was slightly, though significantly, reduced. Inclusion of IFN gamma in the treatment regimen, however, abolished this difference and resulted in complete cure for all 3 tumor systems. As therapeutically optimal doses were lethal in normal mice, only tolerance allowed a long-term cure. We conclude that the influence of tolerance on the anti-tumor activity of TNF as a single agent depends on the tumor type; in combination therapy with IFN gamma, however, tolerance allowed us to dissociate lethal toxicity from anti-tumor activity, irrespective of the tumor type tested.