Redefining Cancer and Immunotherapy Through the Microbiome

Historically, cancer was primarily understood as a disease driven by somatic mutations that disrupt regulatory networks controlling cell cycle progression, apoptosis, and genomic stability. However, growing evidence highlights the critical influence of the tumor microenvironment including immune cells, stromal cells, vasculature, and extracellular matrix components as a dynamic modulator of cancer initiation, progression, and therapeutic response. This evolving paradigm recognizes that cancer is not solely a result of cell-intrinsic genetic alterations but is also shaped by extrinsic factors such as chronic inflammation and physiological stress. These insights underscore the need for integrative approaches that consider both molecular and contextual determinants of malignancy.

Florencia McAllister, MD, a two-time AACR grant recipient, has built her research career around understanding the complex interactions between tumor cells and components of the immune microenvironment such as microbes and metabolites. An unexpected discovery enabled in part by her 2012 Pancreatic Cancer Action Network-AACR Fellowship helped her establish a distinctive research niche at the intersection of tumor immunology, microbiology and cancer biology.

Her early work, supported by the 2012 Fellowship, focused on the role of T-helper (TH17) cells in pancreatic ductal adenocarcinoma (PDAC) and their potential as immunotherapy targets. This research demonstrated that TH17 cell secretion of pro-inflammatory interleukin-17 (IL-17) is essential for the development of early pancreatic neoplasia, providing a rationale for exploring IL-17 inhibition as a preventive strategy.

Building on prior findings that enterotoxigenic Bacteroides fragilis (ETBF) accelerates colonic tumorigenesis via TH17-mediated inflammation in mice, Dr. McAllister sought to investigate whether ETBF colonization could similarly influence the development of pancreatic lesions. In a subsequent project funded by the 2014 Pancreatic Cancer Action Network-AACR Career Development Award, she hypothesized that extra-pancreatic events might drive systemic TH17 immune responses capable of modulating pancreatic cancer risk and progression.

While conducting these studies, Dr. McAllister made a pivotal serendipitous observation: Mice treated with antibiotics showed reduced initiation and delayed progression of malignant pancreatic lesions. This unexpected finding pointed to a critical role for the gut microbiome in modulating PDAC development and progression, opening a new avenue of investigation that continues to define her research trajectory.

Now a professor in the Department of Genetics and Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, Dr. McAllister continues to explore how microbes influence cancer initiation and immunotherapy outcomes; a research trajectory shaped in part by the support of the AACR early in her career. “I think of tumors as small ecosystems that are affected by the host and form part of a larger ecosystem. Early tumorigenesis, tumor progression, and therapy responses are directly or indirectly affected by these ecosystems,” she explains.

Her recent publications in Cancer Immunology Research and Cancer Cell highlight the complexity of IL-17 signaling in pancreatic cancer development and treatment (1, 2). These studies show that systemic IL-17 inhibitors can induce gut dysbiosis and elevate IL-17 production, potentially promoting tumor growth and undermining therapeutic efficacy, offering insights into the limited clinical success of IL-17 neutralization monoclonal antibodies in cancer (3).

Dr. McAllister also co-led a project funded by the 2020 Stand Up to Cancer Phillip A. Sharp Innovation in Collaboration Award, which investigated the genomic and therapeutic implications of bacterial colonization of gastrointestinal cancers. Further, at the AACR Annual Meeting 2024, Dr. McAllister presented findings demonstrating that bacterial burden in tumors can affect therapy responses (4). This work builds on her foundational research and expands the understanding of host-microbe-tumor interactions.

Reflecting on the impact of AACR support, Dr. McAllister shared, “I am grateful for having received the AACR-PanCAN grants early in my career, as it allowed me to focus my research on pancreatic cancer. Beyond the funding, I am especially thankful for the community support as I was able to connect with many other AACR awardees, some of whom are now close collaborators and friends.”

Dr. McAllister’s work exemplifies the shift from a gene-centric model of cancer to a system-level understanding of tumorigenesis. With plans to “tackle a more comprehensive study of tumor ecosystems by integrating different types of information across tumor types and ultimately define actionable targets with immediate translation into patients,” her research continues to challenge traditional paradigms and pave the way for innovative therapeutic strategies. As the field embraces this multidimensional perspective, her contributions stand as foundation for future advances in precision medicine.

References

1. Castro-Pando S, Howell RM, Li L, Mascaro M, Faraoni EY, Le Roux O, et al. Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis. Cancer Immunol Res. 2024;12(9):1170-1183. doi: 10.1158/2326-6066.CIR-23-0527.
2. Chandra V, Li L, Le Roux O, Zhang Y, Howell RM, Rupani DN, et al. Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation. Cancer Cell. 2024;42(1):85-100.e6. doi: 10.1016/j.ccell.2023.12.006.
3. Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, et al. Secukinumab in Crohn’s Disease Study Group. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61(12):1693-700. doi: 10.1136/gutjnl-2011-301668.
4. Hajar Rajaei, Jeong-Hoon Jang, Haoyue Liu, Erika Y. Faraoni, Olivia Le Roux, Vidhi Chandra, et al. Tumor microbial burden is regulated by mast cells and determines immunotherapy responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6673.