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Supplementary Figure 3: Association of chemokine expression with a T cell-inflamed phenotype was validated in a second independent PDAC patient cohort

Supplementary Table 1: Top 99 genes associating with CD8+ TIL counts in primary resected cases

Purpose:The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC.Experimental Design:Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from The Cancer Genome Atlas and 92 PDACs from the Australian International Cancer Genome Consortium. We explored associations between immune cell counts by immunohistochemistry, chemokine expression, and transcriptional hallmarks of antitumor immunity by RNA sequencing (RNA-seq), and mutational burden by whole-genome sequencing.Results:Among all known human chemokines, a coregulated set of four (CCL4, CCL5, CXCL9, and CXCL10) was strongly associated with CD8+ T-cell infiltration (P < 0.001). Expression of this “4-chemokine signature” positively correlated with transcriptional metrics of T-cell activation (ZAP70, ITK, and IL2RB), cytolytic activity (GZMA and PRF1), and immunosuppression (PDL1, PD1, CTLA4, TIM3, TIGIT, LAG3, FASLG, and IDO1). Furthermore, the 4-chemokine signature marked tumors with increased T-cell activation scores (MHC I presentation, T-cell/APC costimulation) and elevated expression of innate immune sensing pathways involved in T-cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T-cell–inflamed phenotype across primary PDAC and PDAC liver metastases.Conclusions:A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.

Acute intraocular pressure (IOP) elevation following repeat intravitreal anti-vascular endothelial growth factor (VEGF) injections (IVI) may pose a risk to the integrity of the retinal nerve fiber (RNFL). This meta-analysis investigates the role of IOP-lowering interventions such as an anterior chamber paracentesis (ACP) and IOP-lowering medications on the IOP in patients undergoing IVIs. MEDLINE, EMBASE, and the Cochrane Library were searched up to February, 2021. Studies investigating IOP-lowering interventions in patients undergoing IVI versus controls were included. The primary outcome was the IOP in the short- and long-term post-IVI. Secondary outcomes were changes in the RNFL thickness and best corrected visual acuity (BCVA). ACP at time of anti-VEGF injection significantly lowered IOP immediately post anti-VEGF (WMD: -27.98 mm Hg, P0.001). Patients in the ACP group also had significantly thicker RNFL compared to control (WMD: 2.07 um, P0.00001) at median follow-up of 16.5 months. IOP-lowering medications (on the day of injection or in the long-term) significantly reduced IOP up to 30 minutes after injection (WMD: -3.31 mm Hg, P = 0.003). This effect was statistically significant between the 2 arms up to 1 month follow-up. There was no difference in BCVA in intervention versus controls. ACP reduces immediate IOP spikes post-IVI and preserves the RNFL in the short- and longterms IOP-lowering medications also reduce IOP spike, with limited data on RNFL thickness.

Idiopathic intracranial hypertension (IIH) is a condition that most often occurs in women of reproductive age with elevated body mass index (BMI) (typical patients). Individuals outside of this demographic group (atypical patients) may have a different pathophysiology underlying raised intracranial pressure (ICP) leading to unique clinical presentations and prognosis.Retrospective chart review of patients with IIH in typical and atypical demographic groups: men, those diagnosed at age 40 or older and those with BMI26.0 kg/m193 typical and 50 atypical patients with IIH were included. Age at diagnosis was higher in men and patients with normal BMI (37.2 ± 11.8 and 32.3 ± 9.8 years versus 27.3 ± 5.6 years). Older patients presented with headache less often than typical patients (42.9% versus 77.2%). Opening pressure on lumbar puncture (LP) and degree of optic disc edema were not significantly different between groups, though men had worse mean deviation (MD) on visual fields (VFs) (10.16 ± 10.40 dB versus 4.52 ± 5.53 dB in typical group). There was no significant difference between the typical and atypical groups in visual outcomes including number of patients requiring surgical treatment, development of optic atrophy and presence of persistent papilledema, though a trend toward worse VF MD was seen in men. In a pooled analysis of all patients, MD on VF at presentation was the only significant predictor of final visual outcome.Men and patients with normal BMI are diagnosed with IIH later in life. Clinical presentations of typical and atypical groups are similar, although older patients report headaches less frequently. Final visual outcomes were not significantly different between typical and atypical patients and VF loss at presentation is the most consistent predictor of final visual outcome in all patients.

Purpose: The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC. Experimental Design: Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from The Cancer Genome Atlas and 92 PDACs from the Australian International Cancer Genome Consortium. We explored associations between immune cell counts by immunohistochemistry, chemokine expression, and transcriptional hallmarks of antitumor immunity by RNA sequencing (RNA-seq), and mutational burden by whole-genome sequencing. Results: Among all known human chemokines, a coregulated set of four (CCL4, CCL5, CXCL9, and CXCL10) was strongly associated with CD8+ T-cell infiltration (P < 0.001). Expression of this “4-chemokine signature” positively correlated with transcriptional metrics of T-cell activation (ZAP70, ITK, and IL2RB), cytolytic activity (GZMA and PRF1), and immunosuppression (PDL1, PD1, CTLA4, TIM3, TIGIT, LAG3, FASLG, and IDO1). Furthermore, the 4-chemokine signature marked tumors with increased T-cell activation scores (MHC I presentation, T-cell/APC costimulation) and elevated expression of innate immune sensing pathways involved in T-cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T-cell–inflamed phenotype across primary PDAC and PDAC liver metastases. Conclusions: A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.

Extramural venous invasion (EMVI) is an independent prognostic factor for prediction of overall unfavorable outcomes in rectal cancer. While EMVI has traditionally been detected in postoperative pathologic specimens, MRI can provide this important piece of information preoperatively. This article reviews the methods of EMVI detection and their clinical implications for treatment and outcomes of rectal cancer. EMVI has fundamental implications for rectal cancer prognosis and long-term outcomes. Since MRI has the advantage of preoperative detection of EMVI, it has been suggested that MRI-detected EMVI be incorporated for preoperative chemoradiotherapy (CRT) treatment stratification of rectal cancer for better patient triage and outcomes.

Pancreatic cancer continues to have the highest mortality rate of all solid cancers, with a 5-year overall survival of approximately 8%. Despite recent progress in other malignancies, immunotherapy remains ineffective against pancreatic cancer. Previous work from our group and others has shown that tumors with mismatch repair (MMR) and homologous repair (HR) deficiency have increased immune activity, likely attributable to the inherently increased mutational and neoantigen load in these patients. However, there remains a subset of pancreatic cancer patients with increased CD8+ T cell infiltration, despite lacking these specific mutational signatures. Furthermore, an increasing body of evidence has shown that mutational burden and neoantigen load only partially explain the T cell-inflamed phenotype seen in tumors, implicating the presence of additional mechanisms that drive T cell infiltration in cancer. Several recent studies have highlighted the importance of proper CD8+ T cell priming by antigen presenting cells (APCs), particularly Batf3+ dendritic cells (DCs), and subsequent tumor infiltration via chemokines for immunotherapy to be effective. In this study, we investigated the involvement of chemokines in cytotoxic T lymphocyte infiltration in pancreatic cancer. Using a bioinformatics-driven approach, we analyzed 78 treatment-naïve, primary pancreas cancer resections for associations between CD8+ tumour infiltrating lymphocytes (TILs) and chemokine expression by RNAseq. A panel of chemokines, including CCL4, CCL5, CXCL9, CXCL10, and CXCL11, was highly associated with CD8+ TILs (p < 0.001). Segregating 173 tumour-enriched patient RNAseq samples based on expression of CXCL9 and CXCL10, we found those with higher expression of these chemokines had increased immune activation signatures. Importantly, this included increased MHC I presentation, presence of Batf3+ DCs, and T cell/APC co-stimulation (p < 0.001), while we observed no differences in conventional predictors of CD8+ T cell infiltration such as SNV counts or neoantigens between groups. These results were consistent across ICGC and TCGA data sets. Moreover, these results were also recapitulated in 72 tumor-enriched liver metastases, suggesting an underlying immunobiology that may occur in both primary and metastatic sites. The cellular sources of these chemokines, as determined by immunohistochemical analysis, and the role of tumor-sensing innate immune pathways leading to CD8+ T cell priming, by pathway and differential gene expression analysis, are currently being investigated. Taken together, these results demonstrate a potential role for these chemokines in recruiting CD8+ T cells in pancreatic cancer. Understanding mediators driving cytotoxic T cell infiltration will help identify mechanisms leading to proper CD8+ T cell priming and homing into tumors, to stratify patients amenable for known and novel immunotherapies. Citation Format: Joan Miguel Romero, Barbara Grünwald, Ashton Connor, Gun Ho Jang, Prashant Bavi, Aaditeya Jhaveri, Mehdi Masoomian, Sandra Fischer, Amy Zhang, Robert E. Denroche, Tracy McGaha, Faiyaz Notta, Pamela Ohashi, Grainne O'Kane, Julie Wilson, Jennifer Knox, Steven Gallinger. Mediators of CD8+ cytotoxic T lymphocyte infiltration in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1500.