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This article explores the potential for enhancing anti-tumor immunity in chemotherapy-treated urothelial carcinoma by targeting the cGAS-STING pathway. The study reveals that while chemotherapies can activate this pathway, it does not always result in the production of type I interferon due to the inhibitory effects of the transcription factor ATF3. The researchers investigated the impact of different chemotherapy combinations on urothelial carcinoma and bladder cancer cell lines and found that while they induced an inflammatory response and markers of immunogenic cell death, they did not effectively activate the immune system. The study provides valuable insights into the mechanisms of chemotherapy-induced immune responses and suggests potential targets for improving anti-tumor immunity in urothelial carcinoma. [Extracted from the article]

Tumor necrosis factor-alpha (TNF-alpha) enhances X-ray killing of human tumor cells in vitro and enhances tumor control when combined with radiotherapy (RT) in animal tumor models. In multiple Phase I studies, intravenous injection of TNF-alpha appeared to have severe systemic side effects. To overcome these limitations, we used a bispecific antibody (BAb) directed against carcinoembryonic antigen and human TNF-alpha to target this cytokine in human digestive carcinoma treated with simultaneous RT. We used human digestive carcinoma cell lines (colon cancer, LS174T, and pancreatic cancer, BxPC-3) to determine the interaction of TNF-alpha and RT on clonogenic cytotoxicity. Isobolograms were established to confirm additive or supra-additive effects between both treatments. LS174T and BxPC-3 cells were grafted subcutaneously at Day 0 into female nude mice (7-8 weeks old). When the tumors reached a volume of about 80 mm(3), the mice were randomly assigned to treatment: Group 1, normal saline i.v. injection (control group); Group 2, TNF-alpha at 1 microg/i.v. injection; Group 3, BAb at 25 microg/i.v. injection; Group 4, BAb plus TNF-alpha (ratio 25 microg to 1 microg) i.v. injection; Group 5, local RT plus normal saline (0.5 Gy. min(-1)) at a total dose of 30 Gy delivered in five fractions; Group 6, local RT plus TNF-alpha injections 3 h before RT; Group 7, local RT plus BAb plus TNF-alpha co-injected 24 h before RT. Tumor growth delay was used as the end point for all groups. In the LS174T experiments, TNF-alpha added 12 h before RT showed a statistically significant decrease in the survival fraction at 2 Gy compared with RT alone (0.23 vs. 0.42 Gy, p = 0.0017). These results were largely confirmed with the BxPC-3 cell lines (0.29 vs. 0.72, p <0.00001). Isobolograms confirmed the additivity between TNF-alpha and RT in both cell lines. At 50% survival, the data points were within the envelope of additivity. In the LS174T and BxPC-3 xenografts, RT as a single agent (Group 5) slowed tumor progression compared with Group 1 (p <0.027 and p = 0.00001, respectively). TNF-alpha alone, BAb alone, or BAb plus TNF-alpha (Groups 2, 3, and 4) had no effect. In the LS174T model, TNF-alpha plus RT enhanced the delay to reach 2000 mm(3) compared with RT alone but without statistical significance. This delay was significantly longer when BAb was added (p = 0.0033, for Group 6 vs. Group 7). In the BxPC-3 experiments, the median delay to reach 2000 mm(3) was similar between the RT and TNF-alpha plus RT groups (93 days). The use of our BAb in combination with TNF-alpha and RT dramatically enhanced this median delay (177 days, p = 0.0013). No body weight loss was observed in any group. Our data could be used as a solid preclinical rationale on which to base a clinical study of locally advanced pancreatic or rectal cancers in the near future.