Generation of tumor-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells (APCs) with innate stimulation. Here we report a minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression. Mechanistically, PC7A NP achieved efficient cytosolic delivery of tumor antigens to APCs in draining lymph nodes leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect was dependent on STING but not Toll-like receptor or MAVS pathway. Nanovaccine produced potent tumor growth inhibition in melanoma, colon cancer, and human papilloma virus-E6/E7 tumor models. Combination of PC7A nanovaccine with an anti-PD-1 antibody showed great synergy with 100% survival over 60 days in a TC-1 tumor model. Rechallenging of these tumor-free animals with TC-1 cells led to complete inhibition of tumor growth, suggesting generation of long-term antitumor memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumor immunity for cancer immunotherapy.

Summary Activation of the DNA-dependent cytosolic surveillance pathway in response to Mycobacterium tuberculosis infection stimulates ubiquitin-dependent autophagy and inflammatory cytokine production, and plays an important role in host defense against M. tuberculosis. However, the identity of the host sensor for M. tuberculosis DNA is unknown. Here we show that M. tuberculosis activated cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) in macrophages to produce cGAMP, a second messenger that activates the adaptor protein stimulator of interferon genes (STING) to induce type I interferons and other cytokines. cGAS localized with M. tuberculosis in mouse and human cells and in human tuberculosis lesions. Knockdown or knockout of cGAS in human or mouse macrophages blocked cytokine production and induction of autophagy. Mice deficient in cGAS were more susceptible to lethality caused by infection with M. tuberculosis. These results demonstrate that cGAS is a vital innate immune sensor of M. tuberculosis infection.

Purpose Non-melanoma skin cancers of the face are at high-risk for local recurrence and metastatic spread. While surgical interventions such as Mohs microsurgery are considered the standard of care, this modality has the potential for high rates of toxicity in sensitive areas of the face. Catheter flap high-dose-rate (HDR) brachytherapy has shown promising results, with high rates of local control and acceptable cosmetic outcomes. Material and methods Patients with non-melanoma skin cancers (NMSC) located on the face were treated with 40 Gy in 8 fractions, given twice weekly via catheter flap HDR brachytherapy. Clinical target volume (CTV) included the visible tumor plus a margin of 5 mm in all directions, with no additional planning target volume (PTV) margin. Results Fifty patients with 53 lesions on the face were included, with a median follow-up of 15 months. All were considered high-risk based on NCCN guidelines. Median tumor size and thickness were 18 mm and 5 mm, respectively. Median PTV volume and D 90 were 1.7 cc and 92%, respectively. Estimated rate of local control at twelve months was 92%. Three patients (5%) experienced acute grade 2 toxicity. Two patients (4%) continued to suffer from chronic grade 1 skin toxicity at 12 months post-radiotherapy (RT), with an additional two patients (4%) experiencing chronic grade 2 skin toxicity. Forty-nine lesions (92%) were found to have a good or excellent cosmetic outcome with complete tumor remission. Conclusions CT-based flap applicator brachytherapy is a valid treatment option for patients with NMSC of the face. This modality offers high rates of local control with acceptable cosmetic outcomes and low rates of toxicity.

Purpose/Objective(s): Incomplete surgery (gross total resection, near total resection, and subtotal resection) of head and neck adenoid cystic carcinoma (HNACC) is controversially considered as an unfavorable prognostic factor as to curative intent surgery (CIS). However, in Intensity-Modulated Radiotherapy (RT) era, after planed incomplete surgery (PIS), intensified RT or RT with concurrent chemotherapy (CCT) may contribute to tumor control and survival. Thus, we investigated the contribution of IMRT after PIS on local control and survival in HNACC. Materials/Methods: Retrospective review was performed for 170 consecutive patients with HNACC treated with curative postoperative IMRT with or without concurrent chemotherapy, between 2015 and 2018, after PIS (n Z 102) or CIS (n Z 68). All plan target volumes were designed to including the primary tumor and related cranial nerve pathway. Patients with other malignant tumors or distant metastasis were excluded. Results: Among the 170 patients (98 women and 72 men; median age, 53 years), the median follow-up time was 27.8 (range, 9.6-59.1) months. The estimated 3-year local-regional recurrence-free survival (LRRFS) rate, progression-free survival (PFS) rate, overall survival (OS) rate, and distant metastasis-free survival (DMFS) rate were 92.4% (95%CI: 87.3-95.9), 74.7% (95%CI: 67.5-81.0), 98.5% (95%CI: 94.9-99.6), and 76.0% (95% CI: 68.7-82.1), respectively. Patients with high grade, Ki-6710%, Stage III-IV, extra-nodal extension (ENE), perineural invasion (PNI) and positive margin was associated with worse PFS (p<0.0001, p Z 0.002, p Z 0.003, and p Z 0.0004, p Z 0.042, and p Z 0.021, respectively). The baseline and treatment characteristics were equally distributed between PIS and CIS group, except that there were more patients with positive margin and received RT dose66 Gy in PIS group (p Z 0.000 and p Z 0.000). There was no difference in LRRFS, DFS, OS, and DMFS between two groups, both in stage I-II and Stage III-IV (p Z 0.280, p Z 0.371, p Z 0.752, and p Z 0.549, respectively). Among patients with high grade, Ki-6710%, ENE or PNI, there was also no difference in PFS between two groups. Among patients received radiation dose<66Gy, PIS group patients had significant worse PFS (p Z 0.029), while among patients without any CCT, PIS group patients had marginal significant worse PFS (p Z 0.067). Conclusion: In IMRT era, PIS does not compromise oncologic treatment, even in patients with worse prognostic factors; however, Doses of 66 Gy or CCT might be essential. This strategy warrants further evaluation in prospective randomized trials with longer follow-up.