(B-65) A Double-Edged Sword; The Enigmatic Role of Hybrid Helper T-cells in Mediating Anti-Tumor Immunity

Introduction:: Introduction: The CD4+ T-cell arm of the adaptive immune system plays a key role in mediating and maintaining anti-tumor immunity. This repertoire consists of a heterogeneous population of subtypes with multifaceted roles including Th1 and Th2, characterized by pro-inflammatory and anti-inflammatory features, respectively. Thus, maintaining a well-balanced Th1 and Th2 response is essential for optimal immune function to avoid tissue damage or allergy. Recent studies have revealed that helper T-cells may acquire hybrid phenotypic states other than the canonical helper T-cell types. However, the functional role and therapeutic value of these phenotypes remains unknown. To shed light on this topic, we developed a data-driven theoretical framework to infer helper T-cell phenotypes from sequencing data and track their dynamics overtime. Understanding the patterns and dynamics of helper T-cell fractions in detail would help with improving the quality and outcome of immunotherapy in cancer patients.


Materials and Methods:: Materials and Methods: Time-course data with helper T cell subsets was used to perform WGCNA. We performed batch correction and network construction which resulted in the identification of modules specific to hybrid phenotypes. We then identified functionally enriched pathways and relevant genes to the modules and proceeded with identifying these phenotypes from tumor sequencing data.


Results, Conclusions, and Discussions:: Results and Discussion: After batch correction and network construction, we identified a module highly associated with the hybrid Th1/2 phenotype. Our analysis demonstrated that Th1/2 cells express a unique set of genes distinct from those expressed in the Th1 and Th2 phenotypes. Specifically, our findings indicate that hybrid Th1/2 cells play a dual role in immune response by promoting leukocyte proliferation and negatively regulating the immune response. We then proceeded with introducing a novel approach to infer these phenotypic states from tumor sequencing data and show that these phenotypic states are associated with patient survival.


Conclusions: Hybrid Th1/2 cells play a dual role in the immune response. We develop a computational framework to infer the dynamics of helper T-cell fractions from sequencing data and associate the expression profiles of phenotypic states to patient survival, highlighting the potential of this approach to improve immunotherapy outcomes in cancer patients.


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