Abstract 5913: Longitudinal blood-based immuno-monitoring reveals distinct immune profiles in colorectal cancer patients with divergent responses to first-line systemic therapy

Abstract Introduction: Peripheral blood mononuclear cells (PBMCs) are key mediators of immune surveillance and response against malignancies. Profiling PBMC subsets provides insights into immune dynamics in cancer progression and therapeutic response, reflecting systemic immune changes that may mirror the tumor microenvironment. This study aimed to identify differences in PBMC profiles between colorectal cancer (CRC) patients deriving clinical benefit from first-line systemic therapy and those with poor outcomes. Methods: We recruited patients with locally advanced, unresectable or metastatic CRC initiating first-line systemic therapy. PBMCs were isolated from venous blood samples at two time points: baseline prior to treatment initiation (L1) and before cycle two of treatment (L2). Flow cytometry was used to assess dynamic changes in immune cell subsets for each patient at L1 and L2. Patients were grouped into Cohort A (clinical benefit: partial response or stable disease ≥6 months) and Cohort B (no clinical benefit: stable disease lasting less than 6 months or progressive disease). The GLIMMIX model was used to compare the differences in cell subset proportions between the two cohorts. Results: Between November 2023 and April 2024, seven patients (median age 64 years, with 71.4% Chinese ethnicity and 57.1% male) were recruited, with four in Cohort A and three in Cohort B. Median progression-free survival was significantly longer in Cohort A (7.0 versus 1.0 months, p=0.029). Immune profiling revealed distinct differences between cohorts. CD4+ T cell subset patterns were suggestive of immune activity potentially associated with better outcomes in Cohort A compared to Cohort B patients; at L1, Cohort A showed increased CD4+ effector memory T cells (p=0.03) while Cohort B displayed a higher proportion of naïve CD4+ T cells (p=0.015). At L2, CD4+ T cell activation, as indicated by Ki67 expression, trended higher in Cohort A (p=0.09), and was accompanied by a lower Treg population (p=0.022). Additionally, patterns of B cell subsets of Cohort B at L2 were consistent with an exhausted immune environment which correlated with poorer prognosis, with Cohort B exhibiting elevated expression of CD38 (p=0.007) and PD-1 (p=0.05) compared to Cohort A. These immune profiles may reflect potential mechanisms underlying early progression and treatment resistance, and warrant further investigation as biomarkers for treatment response in CRC. Conclusions: Dynamic PBMC profiles, particularly CD4+ T cell and B cell subset patterns, show promise as predictive biomarkers for treatment response in advanced CRC. These preliminary findings warrant validation in larger cohorts and highlight the potential of immune profiling to identify patients at risk for early progression, guide therapeutic strategies and improve patient outcomes. Citation Format: Jia Meng, Yong Xiang Gwee, Kai Soon Ng, Wei Peng Yong, Gloria Hui Jia Chan, Hon Lyn Tan, Joan Choo, Robert John Walsh, Jingshan Ho, Joe Yeong, Cheng Ean Chee. Longitudinal blood-based immuno-monitoring reveals distinct immune profiles in colorectal cancer patients with divergent responses to first-line systemic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5913.