Short-Course Radiotherapy Shows Immunologic Advantages in Locally Advanced Rectal Cancer

Key Clinical Takeaways: 

• Short-course radiotherapy is less lymphodepleting than long-course chemoradiotherapy, preserving circulating lymphocyte counts during neoadjuvant treatment.
• Short-course radiotherapy is associated with increased intratumoral CD8+ and FOXP3+ T-cell infiltration, suggesting a more favorable tumor immune microenvironment.
• These immunologic differences support short-course radiotherapy as a rational backbone for neoadjuvant radiation–immune checkpoint inhibitor combinations in locally advanced rectal cancer.

Campbell Roxburgh, MD, University of Glasgow, Glasgow, United Kingdom, discusses findings from a serial sampling study evaluating immune effects of neoadjuvant radiotherapy regimens in patients with locally advanced rectal cancer.

Results showed that short-course radiotherapy was less lymphodepleting than long-course chemoradiotherapy and was associated with higher circulating lymphocytes and greater intratumoral CD8+ and FOXP3+ T-cell infiltration. 

These data support short-course radiotherapy as a more immunologically favorable neoadjuvant platform for combination strategies in locally advanced rectal cancer.

Transcript: 

Hi there, my name is Campbell Roxburgh, I'm a professor of colorectal surgical oncology at the University of Glasgow in the UK, and it's a pleasure to outline our paper recently published in Clinical Cancer Research which Lili Helston was the first author on. 

In this study, we accessed a unique cohort of samples that we built up from patients who were undergoing radiotherapy treatment for locally advanced rectal cancer and we aimed to determine whether there were differences in the immunological parameters in the tumors and in peripheral blood as patients traversed treatment and we used a unique serial sampling protocol in order to do this. 

Patients were recruited to a study where we could have samples taken at endoscopy, prior to initiation of their neoadjuvant therapy, 2 weeks into treatment, 6 weeks into treatment, and then 12 weeks into treatment. And the reason we did this was to try to understand which treatments might be better paired with immunotherapy, which relies on the presence of T cells and checkpoint expression in the immune microenvironment. We hypothesized that there would be a differential effect between the 2 radiotherapy regimens that we use in rectal cancer– these are short-course and long-course chemoradiotherapy, short-course is a hyperfractionated regimen incorporating 5 fractions over 5 days with 5 Gy per fraction, and long-course chemoradiotherapy is over a much longer period of time, up to almost 50 Gy over around 5 and a half weeks, so a lower dose per fraction. The stark differences in these regimens we hypothesized would lead to differences in immune parameters during treatment. 

In our study, we found, using a combination of techniques—RNA-sequencing, multiplex immunofluorescence, peripheral immune cell assessments, and cytokine assessments—that circulating lymphocyte concentrations tended to be more suppressed with long-course chemoradiotherapy regimens compared to short-course radiotherapy regimens. We found that the densities of CD8+ T cells and FOXP3+ T cells were increased after short-course radiotherapy in the tumor compared to long-course chemoradiotherapy. 

We suggested that these changes, taken together, that the immunosuppression related to long-course chemoradiotherapy was present to a lesser degree in short-course radiotherapy and this has implications for studies designing immunotherapy–radiotherapy combinations. We also noted the current and emerging literature, which suggests higher rates of complete response when you combine immune checkpoint blockade with short-course radiotherapy as opposed to long-course chemoradiotherapy, as shown in our recent meta-analysis. 

In conclusion, we suggest that short-course radiotherapy is less lymphodepleting and is associated with greater intratumoral T cell infiltration compared to long-course chemoradiotherapy. These results we think are relevant to the field of radiation–immuno-oncology combination studies in locally advanced rectal cancer, and we think that the results underpin some of the early trial results we've seen in the literature so far.

Source: 

Hillson LVS, McMahon RK, Galbraith NJ, et al. Differential immunologic effects of short-course and long-course radiotherapy in locally advanced rectal cancer. Clin Can Res. Published online: February 3, 2026. doi: 10.1158/1078-0432.CCR-25-2733