Radiation therapy generates extensive cancer cell death capable of promoting tumor-specific immunity. Within the tumor, conventional dendritic cells (cDCs) are known to carry tumor-associated antigens to the draining lymph node (TdLN) where they initiate T-cell priming. How radiation influences cDC migration is poorly understood. Here, we show that immunological efficacy of radiation therapy is dependent on cDC migration in radioimmunogenic tumors. Using photoconvertible mice, we demonstrate that radiation impairs cDC migration to the TdLN in poorly radioimmunogenic tumors. Comparative transcriptional analysis revealed that cDCs in radioimmunogenic tumors express genes associated with activation of endogenous adjuvant signaling pathways when compared with poorly radioimmunogenic tumors. Moreover, an exogenous adjuvant combined with radiation increased the number of migrating cDCs in these poorly radioimmunogenic tumors. Taken together, our data demonstrate that cDC migration play a critical role in the response to radiation therapy.

No abstract

9546 Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma cell line transfected with gp96-Ig fusion protein. Gp96-Ig functions as an antigen chaperone for dendritic cell activation and direct CD8+T cell expansion via cross presentation. DURGA is a multi-cohort study evaluating HS-110 plus anti-PD-1 mAbs in patients (pts) with advanced NSCLC. We report on Cohort A, which enrolled previously-treated pts who had not received an anti-PD(L)1 prior to study entry. Methods: Primary objectives were safety and objective response rate (ORR). Overall Survival (OS) was a secondary endpoint. Pts received 1 X 107 HS-110 cells intradermally every week for 18 wks and nivolumab until tumor progression. To determine cancer testis antigen (CTA) overexpression from baseline pt tumor samples, hybrid-capture RNA-seq libraries were prepared from macrodissected formalin fixed paraffin embedded tumor tissue and sequenced on an Illumina NovaSeq 6000. Gene-level transcripts were quantified using the Salmon software package. Results: 47 pts were enrolled into Cohort A. ORR and clinical benefit rate (CR + PR + SD) were 21% and 43%, respectively, with a 17.2 month median duration of response. Median OS was 28.7 months (mos), with a median follow up of 15.7 mos. One and 2-year survival were 57% and 36%, respectively. A prespecified exploratory analysis of CTA expression level in baseline pt tumor tissue was performed. 50% of pts shared at least 8 of the 39 total antigens overexpressed by HS110. Although there was no difference in ORR between these groups, mOS was higher in pts with tumors that shared ≥ 8 antigens with HS-110 (not reached (NR) [95%CI: 10.3 mos, NR] vs 6.7 mos [95%CI: 1.4 mos, NR]), p = 0.028. Pts whose tumors expressed the ZNF492 antigen also had improved OS (NR [95%CI: 11.6 mos, NR] vs 7.2 mos [95%CI: 1.6 mos, NR]), p = 0.03. All pts experienced at least one adverse event (AE), and the most common AEs were fatigue (28%), arthralgia (19%) and cough (17%). There were 2 grade 5 AEs not related to treatment. Conclusions: The combination of HS-110 and nivolumab appears safe and well tolerated. OS was improved in pts whose tumors express ≥ 8 shared antigens with HS110, as well as in those who specifically expressed ZNF492. Further exploration of antigen expression as a predictor for treatment outcome with HS110 plus nivolumab is ongoing. Clinical trial information: NCT02439450 .

Background Large-scale gut microbiome sequencing has revealed key links between microbiome dysfunction and metabolic diseases such as type 2 diabetes (T2D). To date, these efforts have largely focused on Western populations, with few studies assessing T2D microbiota associations in Middle Eastern communities where T2D prevalence is now over 20%. We analyzed the composition of stool 16S rRNA from 461 T2D and 119 non-T2D participants from the Eastern Province of Saudi Arabia. We quantified the abundance of microbial communities to examine any significant differences between subpopulations of samples based on diabetes status and glucose level. Results In this study we performed the largest microbiome study ever conducted in Saudi Arabia, as well as the first-ever characterization of gut microbiota T2D versus non-T2D in this population. We observed overall positive enrichment within diabetics compared to healthy individuals and amongst diabetic participants; those with high glucose levels exhibited slightly more positive enrichment compared to those at lower risk of fasting hyperglycemia. In particular, the genus Firmicutes was upregulated in diabetic individuals compared to non-diabetic individuals, and T2D was associated with an elevated Firmicutes/Bacteroidetes ratio, consistent with previous findings. Conclusion Based on diabetes status and glucose levels of Saudi participants, relatively stable differences in stool composition were perceived by differential abundance and alpha diversity measures. However, community level differences are evident in the Saudi population between T2D and non-T2D individuals, and diversity patterns appear to vary from well-characterized microbiota from Western cohorts. Comparing overlapping and varying patterns in gut microbiota with other studies is critical to assessing novel treatment options in light of a rapidly growing T2D health epidemic in the region. As a rapidly emerging chronic condition in Saudi Arabia and the Middle East, T2D burdens have grown more quickly and affect larger proportions of the population than any other global region, making a regional reference T2D-microbiome dataset critical to understanding the nuances of disease development on a global scale.

No abstract