Introduction
Immune checkpoint blockade (ICB) for treatment of colorectal cancer (CRC) has been approved for clinical use since 2017. However, the approval of PD-L1 inhibitor for CRC has been encumbered by the lack of durable clinical benefits. Increasing evidence from other cancer types support that PD-L1 expression correlates to the efficacy of ICB and tumor PD-L1 is essential for ICB-mediated tumor cytotoxicity [1-3]. Concomitantly, many studies have also demonstrated the infrequent expression of PD-L1 in CRC cells [4, 5], thereby alluding to the possibility of low/absent PD-L1 expression as a primary obstacle to ICB efficacy.
Aims & Methods
Given the integral role of tumour microenvironment (TME) in shaping the tumour’s natural history, we sought to elucidate the role of tumour stroma in regulating CRC PD-L1 expression. To this end, we aim to rescue tumor PD-L1 and assess its utility in ICB-mediated anti-tumour immunity.
To explore the role of different cell types in the TME on CRC PD-L1 expression, cocultures between major cell compartments of the TME and CRC cell lines were performed. Further various omics approaches were utilised to characterise the crosstalk between CRC and stromal cells that saw significant suppression of CRC PD-L1 expression.
Results
Myeloid cells are able to exert a significant suppression of PD-L1 expression in CRC and this suppression is regulated at a post-transcriptional level. The underlying mechanism is orchestrated by CRC metabolic shift from glycolysis to oxidative phosphorylation in response to harsh metabolic competition within the TME.
Conclusion
We have identified potential cellular compartment of the TME and mechanisms which may explain, in part, low/absent CRC PD-L1 expression. This can thus serve to evaluate appropriate external manipulations that can alleviate CRC PD-L1 suppression and explore the possibility of combinatory therapy with anti-PD-L1 ICB to improve its clinical efficacy and durability.
References
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2. Cortes, J., et al., Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. New England Journal of Medicine, 2022. 387(3): p. 217-226.
3. Lau, J., et al., Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice. Nature Communications, 2017. 8(1): p. 14572.
4. Llosa, N.J., et al., The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints. Cancer Discovery, 2015. 5(1): p. 43-51.
5. Taube, J.M., et al., Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy. Clinical Cancer Research, 2014. 20(19): p. 5064-5074.