Abstract 35P
Background
Type 1 conventional dendritic cells (cDC1) are professional antigen presenting cells and play a critical role in priming cytotoxic CD8+ T cells. DNGR-1 (a.k.a. CLEC9A) is a dedicated cDC1 receptor that binds to F-actin exposed on necrotic cells, signalling to enhance cross-presentation of dead-cell associated antigens. We have recently shown that secreted gelsolin (sGSN), a plasma protein, acts as a negative regulator of DNGR-1 function and dampens anti-cancer immunity (Giampazolias et al. Cell 2021). Here, we investigated the effects of loss of sGSN on various anti-cancer therapies.
Methods
In vivo therapy models were established in C57BL/6 mice: Rag1 –/– (no T/B cells), Batf3 –/– (no cDC1s), sGsn –/–, sGsn –/– Clec9 agfp/gfp and WT (wildtype). Transplantable cell lines used included MCA-205 fibrosarcoma, 5555 BrafV600E melanoma and B16-F10 LA-OVA-mCherry melanoma. Mice received doxorubicin (intratumoural), BRAF-inhibitor PLX4720 (oral gavage), or X-ray irradiation. Bioinformatic analysis of human cancer datasets was done using TCGA Pan-cancer Atlas.
Results
First, we confirmed that tumour control following various therapies requires an immunocompetent host as efficacy was markedly reduced in Rag1 –/– compared to WT mice: (i) MCA-205 + doxorubicin, (ii) 5555 BrafV600E + PLX4720, and (iii) B16-F10 LA-OVA-mCherry + X-ray. Consistently across all these immunogenic therapeutic modalities, loss of sGSN significantly enhanced tumour control compared to treated WT controls. We proved that this is an on-target effect as mice deficient in both sGSN and DNGR-1 behaved similarly to WT mice following therapy. Interrogating n=31 TCGA datasets of solid tumours, we noted that high expression of CLEC9A is associated with better survival in several cancer subtypes.
Conclusions
Utilising preclinical models, we show that mice deficient in sGsn display enhanced responsiveness to chemotherapy, targeted therapy and radiotherapy. Tumours enriched in DNGR-1 may be potential avenues where targeting sGSN could be impactful. Further prospective studies are warranted to identify patients who may benefit most from inhibition of sGSN function to unleash DNGR-1-dependent cross-presentation as a component of more effective combinatorial treatment regimens.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Kok Haw Jonathan Lim and Caetano Reis e Sousa are legally responsible for the governance, coordination and running of the study. K.H.J.L., E.G., O.S., N.C.R. and C.R.S. are named as contributors/inventors on a patent application on the use of sGSN for immunotherapies.
Funding
The Francis Crick Institute, which receives core funding from Cancer Research UK (FC001136), the UK Medical Research Council (FC001136), and the Wellcome Trust (FC001136); an ERC Advanced Investigator grant (AdG 268670); a Wellcome Investigator Award (106973/Z/15/Z); and a prize from the Louis-Jeantet Foundation. K.H.J.L is supported by a Wellcome Imperial 4i Clinical Research Fellowship (216327/Z/19/Z). This research was funded in whole, or in part, by the Wellcome Trust (grants FC001136, 106973/Z/15/Z, and 216327/Z/19/Z).
Disclosure
C. Reis e Sousa: Financial Interests, Personal and Institutional, Member of the Board of Directors, Founder, advisor, stockholder, recipient of research grant: Adendra Therapeutics; Financial Interests, Personal, Advisory Role, Owns stock options and/or paid consultant: Bicara Therapeutics, Montis Biosciences, Bicycle Therapeutics, Sosei Heptares. All other authors have declared no conflicts of interest.