A Diagnostic Biopsy-Adapted Immunoscore Predicts Response to Neoadjuvant Treatment and Selects Patients with Rectal Cancer Eligible for a Watch-and-Wait Strategy

Abstract

Purpose: No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (IS B) could predict response to neoadjuvant treatment (nT) and better define patients eligible to an organ preservation strategy ("Watchand-Wait"). Experimental Design: Biopsies from two independent cohorts (n 1 ¼ 131, n 2 ¼ 118) of patients with LARC treated with nT followed by radical surgery were immunostained for CD3 þ and CD8 þ T cells and quantified by digital pathology to determine IS B. The expression of immune-related genes post-nT was investigated (n ¼ 64 patients). Results were correlated with response to nT and disease-free survival (DFS). The IS B prognostic performance was further assessed in a multicentric cohort (n ¼ 73 patients) treated by Watch-and-Wait. Results: IS B positively correlated with the degree of histologic response (P < 0.001) and gene expression levels for Th1 orientation and cytotoxic immune response, post-nT (P ¼ 0.006). IS B high identified patients at lower risk of relapse or death compared with IS B low [HR, 0.21; 95% confidence interval (CI), 0.06-0.78; P ¼ 0.009]. Prognostic performance of IS B for DFS was confirmed in a validation cohort. IS B was an independent parameter, more informative than pre-(P < 0.001) and post-nT (P < 0.05) imaging to predict DFS. IS B combined with imaging post-nT discriminated very good responders that could benefit from organ preservation strategy. In the "Watch-and-Wait" cohort (n ¼ 73), no relapse was observed in patients with IS B high (23.3%). Conclusions: IS B predicts response to nT and survival in patients with LARC treated by surgery. Its usefulness in the selection of patients eligible for a Watch-and-Wait strategy is strongly suggested.

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“…18 Furthermore, our recent findings in patients with rectal cancer showed a positive association between the signs of local cytotoxic immune activation and the production type-I interferon-associated molecules and the response to neoadjuvant CRT. 45 These results highlight that the effectiveness of CRT relies on its capacity to foster early expansion of functional tumor-reactive CD8+ T cells in the TME.…”

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The Novel CFP Scoring System is a Reliable Marker in Predicting Response and Prognosis in Patients with Locally Advanced Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy

“…First, lymphocytes, especially CD3 + and CD8 + T cells, migrate into the tumor microenvironment of LARC patients and play an essential antitumor role. EL Sissy et al [26] found that the presence of CD3 + and CD8 + T cells was correlated with survival in LARC patients. Second, the level of circulating brinogen is increased by interleukin-6 secreted by tumor cells, and brinogen has been found to interact with several growth factors to induce tumor seeding and promote the invasion of tumor cells, leading to a poor prognosis [27].…”