1039 - CXCL12-Driven Anti-Tumor Neutrophil Infiltration Predicts Pathological Complete Response in pMMR Rectal Cancer Treated with Neoadjuvant SCRT and PD-1 Blockade
Presenter(s)
M. He III1, Y. Chen2, H. Li3, H. Ma1, Y. Zhou4, W. Zhang4, L. Feng4, T. Xu3, J. Chen1, Y. Tang3, D. Li5, Q. Xiao1, and J. Jin4; 1Department of Radiation Oncology, National Cancer Center / National Clinical Research Center for Cancer /Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China, Shenzhen, China, 2State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (PUMC), Beijing, China, 3State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China, 4Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China, 5State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Purpose/Objective(s): The STELLAR II trial (NCT05484024) demonstrated the efficacy of short-course radiotherapy (SCRT) followed by chemotherapy and PD-1 blockade in proficient mismatch repair (pMMR) locally advanced rectal cancer (LARC). While previous cytokine analysis revealed a favorable inflammatory shift—such as increased levels of CXCL12 after SCRT—the cellular drivers of this immune remodeling remain elusive. This study investigates whether specific peripheral anti-tumor neutrophil subpopulations and their intratumoral infiltration patterns can predict pathological complete response (pCR) in pMMR LARC.
Materials/Methods: We analyzed 24 pMMR LARC patients from the STELLAR II experimental arm (SCRT followed by CAPOX/mFOLFOX6 and Sintilimab). Peripheral blood was collected pre-SCRT and 14 days post-SCRT; neutrophil subpopulations were profiled via high-dimensional flow cytometry. For tissue analysis, nine resected surgical specimens underwent multiplex immunofluorescence (mIHC) to quantify infiltrating neutrophils(MPO+/Ly6E+), CD8+ T cells, CD20+ B cells, and PD-1+ cells. Spatial distribution and proximity between neutrophils and the chemokine CXCL12 were analyzed using Panoscore software.
Results: A distinct CD62L+CD66b+ anti-tumor neutrophil subpopulation significantly expanded in peripheral blood 14 days post-SCRT. This expansion was markedly higher in patients achieving pCR compared to non-pCR (p < 0.0002), demonstrating robust predictive value for pCR(AUC=0.95). In resected tissues, pCR patients exhibited dense MPO+ neutrophil infiltration within the tumor regression bed, whereas non-responders showed sparse infiltration in residual tumor areas (p < 0.01). Spatially, these treatment-induced neutrophils significantly co-localized with CXCL12+ regions. CXCL12 expression was significantly elevated in pCR tissues compared to non-pCR tissues (p=0.011), suggesting its role as a key chemoattractant for neutrophil recruitment.
Conclusion: Neoadjuvant SCRT combined with PD-1 blockade orchestrates a systemic-to-local immune response by mobilizing CD62L+CD66b+ anti-tumor neutrophils. These cells are recruited to the TME via the CXCL12 axis, potentially collaborating with anti-tumor neutrophils to mediate tumor regression. Peripheral neutrophil dynamics and spatial intratumoral density serve as robust predictive biomarkers for pCR, offering promising tools for patient selection in organ-preservation strategies for pMMR LARC.