A cross-institutional Journal Club Initiative
The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity.
Ho P. et al. (BioRxiv) DOI: 10.1101/2022.03.21.485049
Tumour infiltrating lymphocytes
CD58 (also known as LFA-3) is a costimulatory receptor that is expressed on antigen-presenting cells and binds to CD2 present on T cells. The CD2-CD58 interaction is important for cell adhesion and recognition, as well as promoting activation and proliferation of T cells.
In this preprint, Ho et al. explore the role CD58 expression can play in cancer immune evasion and the protein-protein interactions CD58 is involved in.
Ho et al. found that melanoma cell lines with CD58 knockout led to significantly reduced tumour lysis and IFN-y production by T cells, whereas overexpression led to increased T cell killing and IFN-y. The CD58 phenotype was found to be mediated by TCR-epitope interactions rather than a non-specific mechanism, and a CD58 interaction with CD2 on T cells was important for cancer cell lysis. Interestingly, use of a CD58-Fc chimera homodimer in combination with CD3 stimulation led to more efficient killing of cancer cells by T cells compared to CD3 stimulation alone.
Applying this work to a mouse model, tumours which were CD58 wild type (WT), knockout, or rescued with CD58 overexpressed, were treated with adoptive cell transfer of tumour infiltrating lymphocytes (TILs). CD58 knockout tumours were resistant to treatment and had significantly lower infiltration compared to the WT, and this was not correlated with tumour size. TILs from CD58 knockout tumours also had lower proliferation rates compared to the WT tumours. CD58 knockout tumours rescued with CD58 overexpression reversed these observations.
Next the authors investigated the protein interactions of CD58. First, they found that CD58 was co-regulated with PD-L1, since loss of CD58 led to PD-L1 upregulation and vice versa. Notably they showed that the CD2 binding site of CD58 was not essential for this co-regulation. The authors then identified CMTM6 as a regulator of CD58, and showed not only that CMTM6 likely shuttles CD58 intracellularly, in a similar fashion to PD-L1, but that CMTM6 mediates the co-regulation between PD-L1 and CD58 and is necessary for PD-L1 increase when there is loss of CD58. Lastly the authors determined that the CMTM6 binding site of PD-L1 was at the N-terminus (aa 20-32).
Confirmed PD-L1 binding site to CMTM6 but would have been interesting to find CMTM6 binding site to PD-L1 as well as to CD58 and whether these regions overlap.
Would have been interesting to measure the binding affinities of CD58 and PD-L1 to CMTM6.
Only CD58 and CMTM6 were knocked out in cell lines, should also carry out PD-L1 knockout to confirm that CD58 would increase as expected.
This preprint shows the importance of the CD58:CD2 axis in T cell responses to cancer cells and how its impairment through CD58 loss can lead to cancer immune evasion even when there is a strong CD2 expression on T cells. The authors also identified that CD58 was co-regulated with PD-L1 and that this was mediated by CMTM6, such that the loss of CD58 led to increase in PD-L1 expression. Overall, this research opens new avenues to improve current immunotherapies either by recruiting and activating CD2-expressing T cells or targeting and disrupting the interactions between CMTM6 and PD-L1.
Reviewed by Max Quastel as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology and the Oxford Centre for Immuno-Oncology (OXCIO) (University of Oxford, GB) and Karolinska Institute’s Center for Infectious Medicine (CIM) & Center for Molecular Medicine (CMM).