Abstract
Chemotherapy modulates the anti-tumor immune response and outcomes depend on the balance of favorable and unfavorable effects of drugs on anti-tumor immunity. 5-Florouracil (5-FU) is widely used in adjuvant chemotherapy regimens to treat colorectal cancer (CRC) and provides a survival benefit. However, survival remains poor for CRC patients with advanced and metastatic disease and immune checkpoint blockade therapy benefits only a sub-set of CRC patients. Here we discuss the effects of 5-FU-based chemotherapy regimens to the anti-tumor immune response. We consider how different aspects of 5-FU’s multi-factorial mechanism differentially affect malignant and immune cell populations. We summarize recent studies with polymeric fluoropyrimidines (e.g., F10, CF10) that enhance DNA-directed effects and discuss how such approaches may be used to enhance the anti-tumor immune response and improve outcomes.
Highlights
Immune surveillance is essential for limiting cancer incidence and an effective anti-tumor immune response is important for maintaining durable remissions in colorectal cancer (CRC) patients with locally advanced and metastatic disease
We summarize evidence that 5-FU modulates the anti-tumor immune response by reducing immunosuppressive cell populations (myeloid-derived suppressor cells (MDSCs), Tregs) and by stimulating immunogenic cell death (ICD,i.e., damaging malignant cells to recruit their phagocytosis by dendritic cells (DCs) and generating an anti-tumor response mediated by effector T-cells
The mortality associated with colon cancer results almost exclusively from metastatic disease
Summary
Immune surveillance is essential for limiting cancer incidence and an effective anti-tumor immune response is important for maintaining durable remissions in colorectal cancer (CRC) patients with locally advanced and metastatic disease. Levamisole is an immune modulating agent [6] that displayed synergy with 5-FU in CRC cells by increasing expression of class I human leukocyte antigens (HLA-1) [7]. There is increasing emphasis on enhancing the anti-tumor immune response thru use of immune-checkpoint blockade (ICB) [13]. While this strategy has impacted outcomes considerably in non-small cell lung cancer (NSCLC) [14], melanoma [15] and other malignancies [16], it has a lesser impact in CRC [17]. It may be possible to harness the anti-tumor immune response more effectively by altering the metabolite distribution of FPs to be more DNA-directed
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