Spatial determinants of response to neoadjuvant radiotherapy and immunochemotherapy in locally advanced mismatch repair proficient rectal cancer

Abstract Although neoadjuvant chemoradiotherapy treatment followed by surgical resection is the recommended treatment for locally advanced rectal cancer (LARC), response rates remain poor. In proficient mismatch repair (pMMR) rectal cancer, combination (vs. monotherapy) immunotherapy has begun to show promise. This study involved 87 LARC patients undergoing short-course radiotherapy (SCRT), followed by CAPOX (capecitabine and oxaliplatin), in combination with the immune checkpoint inhibitor tislelizumab. Following neoadjuvant therapy, 81 patients underwent surgery, achieving an R0 resection rate of 98.7%. Pathological complete response (pCR) was observed in 41 patients (50.6%), with responders (patients with tumor regression grade TRG 0/TRG 1 or complete clinic response) constituting 69% (60/87). Grade 3 adverse events occurred in 11.5% of participants, and there was one case of grade 4 myasthenia gravis. Imaging Mass Cytometry (IMC) analysis demonstrated higher infiltration of M1 macrophages were in responders. Spatial analysis further identified significant aggregation of PD-L1+ myofibroblastic cancer-associated fibroblasts (MyoCAFs), a unique cell population, within a 10 µm radius to tumor cells, in non-responders; and dynamic analysis showed that post-treatment PD-L1+ MyoCAFs continued to increase in the non-responder group, who also had more exhausted CD8+T cells, possibly explaining their worse response. Our study affirms the efficacy and safety of neoadjuvant SCRT combined with immunochemotherapy in LARC, highlighting the importance of assessing the spatial distribution of immune cells in the tumor microenvironment (TME) for predicting treatment responses. ClinicalTrials.gov registration: NCT05515796.