A type I interferon footprint in pre-operative biopsies is an independent biomarker that in combination with CD8+ T cell quantification can improve the prediction of response to neoadjuvant treatment of rectal adenocarcinoma.

Tailored treatment for patients with rectal cancer requires clinically available markers to predict their response to neoadjuvant treatment. The quantity of tumor-infiltrating lymphocytes (TILs) in pre-operative tumor biopsies has been suggested to predict a favorable response, but opposing results exist. A biopsy-adapted Immunoscore (IS_B) based on TILs has recently emerged as a promising predictor of tumor regression and prognosis in (colo)rectal cancer. We aimed to refine the IS_B for prediction of response using multiplex immunofluorescence (mIF) on pre-operative rectal cancer biopsies. We combined the distribution and density of conventional T cell subsets and γδT cells with a type I Interferon (IFN)-driven response assessed using Myxovirus resistance protein A (MxA) expression. We found that pathological complete response (pCR) following neoadjuvant treatment was associated with type I IFN. Stratification of patients according to the density of CD8⁺ in the entire tumor tissue and MxA⁺ cells in tumor stroma, where equal weight was assigned to both parameters, resulted in improved predictive quality compared to the IS_B. This novel stratification approach using these two independent parameters in pre-operative biopsies could potentially aid in identifying patients with a good chance of achieving a pCR following neoadjuvant treatment.