Debra Tross

Autoimmune diseases, immune-mediated inflammatory diseases, and cancer are distinct pathological conditions that can intersect through immune dysregulation, chronic inflammation, impaired host defense, and altered host–microbe interactions. In selected settings, autoimmune and immune-mediated inflammatory diseases are associated with increased gastrointestinal cancer risk. Although bacterial and viral contributions to inflammation-associated cancer have been extensively studied, the role of fungi remains less investigated. This Opinion article discusses host–fungus interactions through two experimental mouse models that connect altered immune tolerance, innate antifungal responses, and gastrointestinal tumorigenesis. Kinase-dead IKKα K44A knock-in mice develop defective central immune tolerance, APECED-like autoimmune manifestations, mucosal fungal infection, epithelial EGFR signaling, and esophageal squamous cell carcinoma. By contrast, Card9^−/− mice provide a distinct model in which impaired innate antifungal immunity alters intestinal fungal ecology and myeloid-cell responses in colitis-associated colorectal cancer. In the CARD9 setting, fungi may exert pathogenic or protective effects depending on host genotype, immune context, fungal species, and mycobiome structure. Together, these models provide useful tools for investigating how fungi may contribute to gastrointestinal tumorigenesis through cancer-promoting inflammation and immune suppression in a context-dependent manner. However, these findings do not yet validate clinical strategies and should not be interpreted as broadly representative of all autoimmune or immune-mediated inflammatory diseases. Further mechanistic and human studies are needed.

Fungi have been detected within human tumors and shown to support tumor progression. A better understanding of how intratumoral fungi evade innate immunity, remodel the tumor microenvironment (TME), and promote tumorigenesis may provide insights into cancer pathogenesis and therapeutic strategies. In this study, we showed that aggressive human head and neck squamous cell carcinomas (HNSCC) harbor an elevated fungal burden, including the environmental fungus Cladosporium cladosporioides, and are infiltrated by IL1B-high neutrophils with impaired reactive oxygen species (ROS) production and phagocytosis, as well as IL1B-high macrophages. In a mouse model in which Ikka ablation drives tumorigenesis through EGFR and STAT3 activation, oral C. cladosporioides infection recapitulated key features of the human HNSCC TME, elevated serum IL1β and IL17A levels, and promoted both oral and skin SCC development. Oral fungal infection also increased the acidic metabolites uric acid and lactate in the TME. These metabolites enhanced C. cladosporioides–induced IL1β production while reducing ROS production in neutrophils, thereby impairing fungal clearance. Mechanistically, C. cladosporioides, IL1β, and IL17A activated STAT3 and cyclin D1 signaling in SCC cells. Epithelial Stat3 deletion abrogated both Ikka loss-driven and fungus-enhanced oral and skin carcinogenesis, reduced macrophage accumulation, restored normal oral neutrophil phenotypes, and cleared oral fungal infection. Furthermore, IL1β induced by C. cladosporioides inoculation drove systemic inflammation that promoted skin SCC via an IL1β/IL1R feedback loop involving neutrophils and macrophages. Together, these findings identify a fungus-driven immunosuppressive circuit in which tumor-derived acidic metabolites impair antifungal immunity, thereby promoting both local and distal SCC progression. Significance: Fungal infections enhance IL1β production and STAT3 signaling to promote infiltration of inflammatory neutrophils and macrophages that support squamous cell carcinoma progression, providing promising targets for cancer treatment and prevention.

Toll-like receptor (TLR) 7/8 and 9 agonists stimulate an innate immune response that supports the development of tumor-specific immunity. Previous studies showed that either agonist individually could cure mice of small tumors and that when used in combination, they could prevent the progression of larger tumors (>300 mm³). To examine whether these agents combined could control metastatic disease, syngeneic mice were challenged with the highly aggressive 66cl4 triple-negative breast tumor cell line. Treatment was not initiated until pulmonary metastases were established, as verified by bioluminescent imaging of luciferase-tagged tumor cells. Results show that combined therapy with TLR7/8 and TLR9 agonists delivered to both primary and metastatic tumor sites significantly reduced tumor burden and extended survival. The inclusion of cyclophosphamide and anti-PD-L1 resulted in optimal tumor control, characterized by a 5-fold increase in the average duration of survival.

Urothelial cell carcinoma is the most common cancer of the renal pelvis or ureter in humans. Due to a lack of animal models, its pathogenic causes remain elusive. Here, we generated Ikkα^ΔKsp mice lacking Ikkα specifically in epithelial cells of the developing kidney and genitourinary tract as well as renal tubules. The mutant mice developed invasive papillary urothelial cell carcinomas initiated from the pelvis, leading to hydronephrosis, and the animals eventually died. Depleting neutrophils or antibiotic treatment slowed down the development of phenotypes but did not rescue them, suggesting that epithelial-cell-autonomous aberrant alterations induced by Ikkα loss are critical for the initiation of urothelial cancer. Moreover, We found that the urothelial cell carcinomas in the mutant mice highly expressed cancer stem-cell markers such as Sox2, K15, p63, Nanog, and CD44, as well as FGFR3 and osteopontin (OPN). Thus, we hypothesize that Ikkα ablation-mediated OPN and FGFR3 overexpression regulates and amplifies CD44⁺ renal cancer-stem cells for tumor initiation. These alterations are shared with human papillary urothelial cell carcinomas. Citation Format: Xin Li, Feng Zhu, Chengfei Jiang, Yongmei Zhao, Bao Tran, Donna Butcher, Xiaolin Wu, Tross Debra, Yinling Hu. IIKKa deletion amplifies renal transitional epithelial stem cells and initiates lethal invasive papillary urothelial cell carcinoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 926.

Adjuvants improve host responsiveness to co-delivered vaccines through a variety of mechanisms. Agents that trigger cells expressing Toll-like receptors (TLR) activate an innate immune response that enhances the induction of vaccine-specific immunity. When administered in combination with vaccines designed to prevent or slow tumor growth, TLR agonists have significantly improved the generation of cytotoxic T lymphocytes. Unfortunately, vaccines containing TLR agonists have rarely been able to eliminate large established tumors when administered systemically. To improve efficacy, attention has focused on delivering TLR agonists intra-tumorally with the intent of altering the tumor microenvironment. Agonists targeting TLRs 7/8 or 9 can reduce the frequency of Tregs while causing immunosuppressive MDSC in the tumor bed to differentiate into tumoricidal macrophages thereby enhancing tumor elimination. This work reviews pre-clinical and clinical studies concerning the utility of TLR 7/8/9 agonists as adjuvants for tumor vaccines.

The TLR7/8 agonist 3M-052 and the TLR9 agonist CpG ODN both trigger innate immune responses that support the induction of tumor-specific immunity. Previous studies showed that these agonists used individually could improve the survival of mice challenged with small tumors but were of limited therapeutic benefit against large/advanced tumors.