Harshyne, L. A. | Search bioRxiv

bioRxiv2024

Tumor microenvironment governs the prognostic landscape of immunotherapy for head and neck squamous cell carcinoma: A computational model-guided analysis

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. An exhaustive simulation of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8+ killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.

cancer biology↗

bioRxiv2021

Multimodal genomic markers predict immunotherapy response in the head and neck squamous cell carcinoma

Immune checkpoint blockade (ICB) therapy has had a major impact on the clinical management of head and neck squamous cell carcinoma (HNSCC). However, clinical responses to ICB are observed in only a fraction of patients. In the present paper, we used multimodal approaches to a) evaluate the utility of existing ICB biomarkers including tumor mutation burden (TMB), microsatellite instability (MSI), and a T-cell specific signature in predicting therapy response in HNSCC using TCGA cohort, and; b) identify a novel molecular signature to predict ICB therapy response using an ICB clinical trial of HNSCC. Our results confirm previous reports showing TMB efficacy as a biomarker and its outcome can be influenced by age, tumor sub-site, and smoking status; and that High-TMB and high-MSI tumors are associated with T-cell signature, and better survival probability in the HNSCC. We go on to demonstrate that High-TMB and high-MSI utilizes cell-cycle/cell proliferation processes for their molecular functionality; and identify a novel Cell Proliferation ICB-therapy Predicting (CPIP) signature capable of predicting ICB therapy response in HNSCC, retrospectively, where traditional biomarkers of ICB response were insufficient. In summary, the present study defines strategies and novel signatures that can be appropriately used for patient selection for ICB therapy that can improve the clinical outcomes of HNSCC patients.

genomics↗