Tumor Immune Microenvironment and Response to Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer: Results From the STAR-01 Study Cohort.

Abstract

Purpose: Preoperative chemoradiotherapy (CRT) can reshape the composition of the tumor immune microenvironment (TIME) in locally advanced rectal cancer (LARC), augmenting T-cell density and activation. As TIME may provide predictive insights, we analyzed the association of immune cell distribution and remodeling after CRT with pathologic response and clinical outcomes in patients with LARC derived from the STAR-01 (fluorouracil-based CRT plus/minus oxaliplatin) trial.

Patients and methods: Tumor-infiltrating lymphocytes (TILs) were assessed by standard stains and immunostains (CD3, CD20, CD4, CD8, FOXP3, PD-1, and CD68). Immune cell populations in pretreatment biopsies and post-treatment surgical specimens were compared and associated with complete pathological response (ypT0N0) and overall (OS) and event-free (EFS) survival.

Results: We retrieved 413 samples from 303 patients from the original cohort, including 110 paired pretreatment biopsies and post-treatment surgical tumor specimens. In pretreatment biopsies, CD20⁺ cell counts were associated with improved EFS (P = .051), independent of other prognostic factors. After therapy, intermediate-high TILs, CD3⁺ cells, low CD4⁺/CD8⁺ ratio, and CD68⁺ macrophage counts significantly increased, whereas FOXP3⁺ and CD20⁺ cells decreased. ypT0N0 was associated with low CD4⁺/CD8⁺ ratio (P < .001), reduced CD68⁺ (P = .001), and absence of eosinophils (P < .001) in post-treatment surgical specimens. In post-treatment specimens, low CD4⁺/CD8⁺ ratio and CD20⁺ cell counts were significantly associated with both improved EFS (CD4⁺/CD8⁺: P = .016; CD20⁺ cells: P = .002) and OS (CD4⁺/CD8⁺: P = .005; CD20⁺ cells: P = .014). This prognostic role was confirmed in a multivariable analysis for CD20⁺ cells.

Conclusion: In LARC, CRT reshapes the type and amount of immune cell contents, and the effects on certain immune populations are associated with tumor regression and clinical outcome.