Combining an alarmin HMGN1 peptide with PD-L1 blockade facilitates stem-like CD8+ T cell expansion and results in robust anti-tumor effects
Chen* et al. (BioRxiv) DOI: 10.1101/2020.12.15.422990
Immune Checkpoint Blockade
CD8 T cells
In this preprint, Chen et al. study the synergistic effect of HMGN1 and minP1, a HMGN1-derived short synthetic peptide, in combination with anti-PD-L1 therapy in four murine models of cancer. Observations made in this preprint recapitulate previous findings that HMGN1 or its derived peptides may improve antitumor immunity (cf. Nie et al., Scientific Reports 2016; Chen et al. J Immunother Cancer 2019). Conducting bulk RNAseq of whole tumor samples as well as scRNAseq of tumor-infiltrating immune cells, the authors propose that antitumor properties of minP1 (HMGN1) are mediated by enhanced recruitment of tumor-infiltrating mregDCs via MHC-I pathways as well as by their interaction with precursor exhausted CD8 T cells (SLAMF6+/TIM-3-).
Overall, the experiments performed in this study are technically well conducted. However, some limitations need to be addressed:
Apart from the antitumor properties mediated by minP1/anti-PD-L1, this study provides little functional data and the proposed mode of action of minP1 (HMGN1) on tumor-infiltrating CD8 T cells and DCs remains vague but for a “CellPhoneDB” predicted interaction analysis. Similarly, it would be relevant to evaluate minP1/anti-PD-L1 combination therapy in the context of tumor-infiltrating antigen-specific instead of bulk CD8 T cells and to also conduct an expanded phenotypical analysis beyond the co-expression of SLAMF6 and TIM-3.
Importantly, the observations made here regarding the benefit of minP1 (HMGN1)/anti-PD-L1 combination therapy in murine cancer models are not adequately discussed in the context of previously published similar work by this group as well as others (cf. Oppenheim, J. and Yang, D., US Patent Filed, application number 62/355, filed 27 June 2016; Nie Y et al., Development of a Curative Therapeutic Vaccine (TheraVac) for the Treatment of Large Established Tumors. Sci Rep 7, 14186 (2017)).
Methodological details, e.g. why is HMGN1 (minP1) treatment initiated on day 9, but anti-PD-L1 is already applied on day 4 post tumor inoculation.
Combining anti-PD-L1 therapy with HMGN1 (or a synthetic HMGN1 peptide) may enhance overall antitumor efficacy of immune checkpoint blockade and thus be a promising strategy to overcome immunosuppression in refractory cancers.
Reviewed by Verena Van Der Heide as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.