Differential Immunologic Effects of Short-Course and Long-Course Radiotherapy in Locally Advanced Rectal Cancer

Area of Science:

• Radiation oncology
• Immunology
• Gastrointestinal oncology

Background:

• Locally advanced rectal cancer (LARC) treatment often involves neoadjuvant radiotherapy (RT).
• Two common RT regimens are long-course radiotherapy (LCRT) and short-course radiotherapy (SCRT).
• Understanding the immune response to different RT regimens is crucial for optimizing cancer treatment.

Purpose of the Study:

• To investigate the systemic and local immune responses to LCRT versus SCRT in LARC patients.
• To compare the evolution of immune cell populations and T cell infiltration between the two RT regimens.

Main Methods:

• Serial sampling of blood and tumor biospecimens from LARC patients undergoing LCRT or SCRT.
• Measurement of leukocyte concentrations and plasma cytokines to assess systemic immune changes.
• Analysis of tumor biopsies for CD8+ and FOXP3+ T cell infiltration using multiplex immunofluorescence and RNA-sequencing.

Main Results:

• SCRT patients showed a trend towards increased circulating lymphocytes, while LCRT patients showed a decrease.
• LCRT patients had significantly lower lymphocyte concentrations at weeks 6 and 12 compared to SCRT patients.
• SCRT was associated with higher densities of intra-tumoral CD8+ and FOXP3+ T cells compared to LCRT.

Conclusions:

• SCRT demonstrates less lymphodepletion and promotes greater intra-tumoral T cell infiltration compared to LCRT.
• These findings support the use of SCRT-based regimens in combination with immunotherapy for LARC.
• The differential immune response may explain improved outcomes observed in trials combining SCRT with immune checkpoint inhibitors.