Abstract 1523: The predictive potential of gamma-delta T cells and germinal B cells in cancer therapy for enhanced clinical outcomes

Abstract Introduction: Immune Checkpoint Blockade (ICB) therapy elicits clinical responses in a subset of patients in multiple cancer types, yet predicting response remains an open problem. While CD8-T cells remains to be focus, emerging evidence suggests role of other immune cell subtypes in favorable outcome of patients. This study presents the abundance of gamma-delta T (gdt) cell subpopulations in responders and non-responders. The analysis further contrasts differential abundances under immunotherapy and non-immunotherapy regimens across diverse cancers. Methods: We performed joint analysis of data from 250 non-immunotherapy cohorts and 17 ICB cohorts. To infer differential abundance in each cohort, we first identified genes robustly upregulated in tumors of patients with favorable outcome, and then unbiasedly evaluated upregulated genes for enrichment for immune cell populations. The topmost differential abundant subpopulations were validated by de novo assembly and single cell analyses. Results: Our analysis revealed similarities in the immune microenvironment across responders, irrespective of immunotherapy or non-immunotherapy modalities, strongly suggesting shared factors influencing response. Notably, gdt cells emerged as consistent predictors of better prognosis, being associated with favorable responses to ICB therapy and improved long-term survival in non-immunotherapy-treated cancer patients. Two independent validation approaches reinforce these findings. First, taking advantage of the fact that gamma and delta receptors are unique to gdt cells, we obtained precise estimates of gdt cells in tumors from their RNA-seq using de novo assembly. The assessment recapitulated our finding that favorable prognosis of tumors with of gdt cell levels. Second, analysis of several single-cell RNA-sequencing cohorts showed that patients with favorable prognoses consistently exhibit high gdt cell levels within tumors. Conclusion: The study underscores a strikingly consistent responder immune microenvironment, whether under immunotherapy or non-immunotherapy setting, suggesting a shared response and resistance mechanisms. The likelihood of cross-resistance has implications when clinicians decide whether immunotherapy should be administered before or after the traditional therapies for patients. Our study also elucidates the role of gdt cells as potent biomarkers for ICB therapy and their broader significance in enhancing patient survival across various cancer types. Ultimately, these insights may refine patient selection and inform tailored treatment strategies, could elevating clinical outcomes in the realm of precision oncology. Citation Format: Aaron Segura, Mikaela Dicome, Li Song, Xiaole Shirley Liu, Avinash Sahu. The predictive potential of gamma-delta T cells and germinal B cells in cancer therapy for enhanced clinical outcomes [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 1523.