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Type 1 conventional dendritic cells (cDC1) play a critical role in priming anticancer cytotoxic CD8+ T cells. DNGR-1 (a.k.a. CLEC9A) is a cDC1 receptor that binds to F-actin exposed on necrotic cancer and normal cells. DNGR-1 signaling enhances cross-presentation of dead-cell associated antigens, including tumor antigens. We have recently shown that secreted gelsolin (sGSN), a plasma protein, competes with DNGR-1 for binding to dead cell-exposed F-actin and dampens anticancer immunity. Here, we investigated the effects of loss of sGSN on various anticancer therapies that are thought to induce cell death and provoke an immune response to cancer. We compared WT (wildtype) with Rag1–/–, Batf3–/–, Clec9agfp/gfp, sGsn–/– or sGsn–/– Clec9agfp/gfp mice implanted with transplantable tumor cell lines, including MCA-205 fibrosarcoma, 5555 BrafV600E melanoma and B16-F10 LifeAct (LA)-ovalbumin (OVA)-mCherry melanoma. Tumor-bearing mice were treated with (1) doxorubicin (intratumoral) chemotherapy for MCA-205, (2) BRAF-inhibitor PLX4720 (oral gavage) targeted therapy for 5555 BrafV600E, and (3) X-ray radiotherapy for B16 LA-OVA-mCherry. We confirmed that efficient tumor control following each therapy requires an immunocompetent host as efficacy was markedly reduced in Rag1–/– compared with WT mice. Notably, across all the therapeutic modalities, loss of sGSN significantly enhanced tumor control compared with treated WT controls. This was an on-target effect as mice deficient in both sGSN and DNGR-1 behaved no differently from WT mice following therapy. In sum, we find that mice deficient in sGsn display enhanced DNGR-1-dependent responsiveness to chemotherapy, targeted therapy and radiotherapy. Our findings are consistent with the notion some cancer therapies induce immunogenic cell death (ICD), which mobilizes anticancer T cells. Our results point to cDC1 and DNGR-1 as decoders of ICD and to sGSN as a negative regulator of such decoding, highlighting sGSN as a possible target in cancer treatment. Further prospective studies are warranted to identify patients who may benefit most from inhibition of sGSN function.

Background Short–term topical application of a Toll-like receptor 7 (TLR7) agonist, Imiquimod (IMQ), is a widely used murine model of psoriasis. Recently long–term epicutaneous application (4–8 weeks) of IMQ has been shown to elicit lupus-like manifestations. Importantly the topical application of IMQ induced more potent systemic effects than the intraperitoneal administration, indicating that activation of the TLR7-signalling in the skin plays a key role. Objectives Since complement activation is known to have a crucial role in the regulation of local inflammation and in the pathogenesis of lupus, we investigated whether C3 played a role in the induction of the cutaneous lesions as well as in the lupus-like syndrome triggered by IMQ Methods BALB/c wild-type (WT) and C3-deficient (BALB/c.C3 –/– ) mice were treated with topical application of 5% IMQ cream for either 7 consecutive days (short-term) or 3 days /week for 11 weeks (long-term). Results After 7 days, skin thickening (ear thickness at day 7: WT 60.14 mm ± 1.625, n=7, vs BALB/c.C3 –/– 50.88 mm ± 2.460, n=8, p value=0.0094) and local neutrophil recruitment (cell number at day 7: 52.3±6.736, n=7, vs BALB/c.C3 –/– 30.33±4.192, n=7, p value=0.0170) were significantly reduced in the absence of C3. The expansion of IL17 + γδ + T cells in the draining lymph nodes was also significantly impaired (day 7: WT 59.06% ± 2.961, n=7, vs BALB/c.C3 –/– 46.21% ± 2.023, n=8, p value=0.0029 ) . Long-term IMQ treatment resulted in the development of similar low titres of auto-antibodies in both groups of mice (anti-RNP: WT 29.75±11.33, n=5 vs BALB/c.C3 –/– 97.28±41.53, n=5, p=0.1553; anti-ssDNA: WT 9.252±3.367, n=5, vs BALB/c.C3 –/– 20.70±12.03, n=5, p=0.386; anti-chromatin: WT 12.59±7.001, n=5, vs BALB/c.C3 –/– 16.72±12.60, n=5, p=0.781). In addition, the kidney histology scored by a trained histopathologist evidenced no difference in the glomerulonephritis severity. Conclusions Collectively, these data suggest that C3 acts as a potential mediator of IMQ-induced skin inflammation. However, the different local tissue response does not result in an altered autoimmune response in the C3-deficient mice. The study of the involvement of other complement components is currently in progress. Disclosure of Interest None declared