Immunogenic cell death by neoadjuvant oxaliplatin and radiation protects against metastatic failure in high-risk rectal cancer

Simer J Bains,Kathrine Røe Redalen,Anne Hansen Ree,Svein Dueland,Sebastian Meltzer,Kjersti Flatmark,Knut H Hole,Therese Seierstad,Hanna Abrahamsson

doi:10.1007/s00262-019-02458-x

Abstract

ObjectiveHigh rates of systemic failure in locally advanced rectal cancer call for a rational use of conventional therapies to foster tumor-defeating immunity.MethodsWe analyzed the high-mobility group box-1 (HMGB1) protein, a measure of immunogenic cell death (ICD), in plasma sampled from 50 patients at the time of diagnosis and following 4 weeks of induction chemotherapy and 5 weeks of sequential chemoradiotherapy, both neoadjuvant modalities containing oxaliplatin. The patients had the residual tumor resected and were followed for long-term outcome.ResultsPatients who met the main study end point—freedom from distant recurrence—showed a significant rise in HMGB1 during the induction chemotherapy and consolidation over the chemoradiotherapy. The higher the ICD increase, the lower was the metastatic failure risk (hazard ratio 0.26, 95% confidence interval 0.11–0.62, P = 0.002). However, patients who received the full-planned oxaliplatin dose of the chemoradiotherapy regimen had poorer metastasis-free survival (P = 0.020) than those who had the oxaliplatin dose reduced to avert breach of the radiation delivery, which is critical to maintain efficient tumor cell kill and in the present case, probably also protected the ongoing radiation-dependent ICD response from systemic oxaliplatin toxicity.ConclusionThe findings indicated that full-dose induction oxaliplatin followed by an adapted oxaliplatin dose that was compliant with full-intensity radiation caused induction and maintenance of ICD and as a result, durable disease-free outcome for a patient population prone to metastatic progression.

Highlights

The potential to use the immune system to fight progressing cancer has opened new therapeutic avenues
Baseline high-mobility group box-1 (HMGB1) was not associated with patient or tumor characteristics (Table 1)
Analysis of tumor gene expression data sets has shown that mutant KRAS status is associated with reduced infiltration of cytotoxic T cells and suppression of the adaptive IFN-γ response in colorectal cancer (CRC) [30], and a possible mechanism for mutant KRAS-driven CRC immune tolerance was recently reported [31]

Summary

Introduction

The potential to use the immune system to fight progressing cancer has opened new therapeutic avenues. Tumor-defeating immunity depends on both tumor-antigen recognition and the action of cytotoxic T cells, but is counterbalanced by tumor-induced immune tolerance The latter can be edited by cancer immune therapies that revoke the evading T cell cytotoxicity. This concept has proven successful in the treatment of a limited number of immunogenic tumors. Less immunogenic cancers, such as the majority of colorectal cancer (CRC) cases, will need additional stimulation to breach the immune tolerance in order for patients to achieve beneficial therapeutic responses [1]. Within this frame of reference, immunogenic cell death (ICD) implies the cytotoxic damage of tumor cells by either radiation or certain systemic remedies and the resulting priming of tumor-targeting T cells [2]

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Results

Conclusion