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How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood. Here, we integrate DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 squamous cell lung cancer (SCC) patients. We identify three proteomic subtypes, two of which (Inflamed, Redox) comprise 87% of tumors. The Inflamed subtype is enriched with neutrophils, B-cells, and monocytes and expresses more PD-1 . Redox tumours are enriched for oxidation-reduction and glutathione pathways and harbor more NFE2L2/KEAP1 alterations and copy gain in the 3q2 locus. Proteomic subtypes are not associated with patient survival. However, B-cell-rich tertiary lymph node structures, more common in Inflamed, are associated with better survival. We identify metabolic vulnerabilities ( TP63 , PSAT1 , and TFRC ) in Redox. Our work provides a powerful resource for lung SCC biology and suggests therapeutic opportunities based on redox metabolism and immune cell infiltrates.

Purpose: Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase 1/1b trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non-small cell lung cancer (NSCLC).Experimental Design: Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens.

Kaposi sarcoma (KS) is an uncommon angioproliferative malignancy that is associated with human herpesvirus 8. Although there has been recent enthusiasm for evaluating immune checkpoint inhibition as a therapeutic option for viral-associated tumors, the clinical utility in this disease is currently unknown. We report a case of advanced classic KS refractory to multiple lines of chemotherapy that experienced a partial response to anti-PD-1 therapy. Comprehensive molecular profiling was performed on a diagnostic tumor biopsy sample. Molecular profiling data from 8 additional male patients with KS were reviewed and compared with those of the index case. The genomic profile of the index case was notable for higher-than-typical somatic mutational burden, including pathogenic mutation in multiple well-described cancer genes, such as , and Our case suggests that further clinical study of checkpoint inhibitor therapy in classic KS is warranted, and provides a hypothesis for future immunogenomic biomarker analysis in this disease.

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Background Immunotherapy yields survival benefit some advanced stage non-small cell lung cancer (NSCLC) patients. Since highly predictive biomarkers of immunotherapy response are an unmet clinical need, we utilized pre-treatment radiomics and clinical data to train and validate a parsimonious model associated with survival outcomes among NSCLC patients treated with immunotherapy. Methods Three cohorts of NSCLC patients treated with immunotherapy were analyzed: Training (N = 180), validation 1 (N = 90) and validation 2 (N = 62). The most informative clinical and radiomic features were subjected to decision tree analysis which stratified patients into risk groups of low-, moderate-, high-, and very-high-risk of death after initiation of immunotherapy. All statistical tests were two-sided. Results The very-high-risk group was associated with extremely poor overall survival (OS) in validation cohorts 1 (hazard ratio [HR]=5.35; 95% confidence interval [CI]=2.14–13.36, 1-year OS = 11.1%; 95% CI = 1.9–29.8, 3-year OS = 0%) and 2 (HR = 13.81; 95% CI = 2.58–73.93, 1-year OS = 47.6%; 95% CI = 18.2–72.4, 3-year OS = 0%) when compared to the low-risk group (HR = 1.00) in validation cohorts 1 (1-year OS = 85.0%; 95% CI = 60.4%–94.9%, 3-year OS = 38.9%; 95% CI = 17.1%–60.3%) and 2 (1-year OS = 80.2%; 95% CI = 40.3%–94.8% and 40.1%; 3-year OS = 40.1%; 95% CI = 1.3%–83.5%). The most informative radiomic feature, GLCM inverse difference, was positively associated with hypoxia-related carbonic anhydrase 9 using gene-expression profiling and Immunohistochemistry. Conclusion Utilizing standard-of-care imaging and clinical data, we identified and validated a novel parsimonious model associated with survival outcomes among NSCLC patients treated with immunotherapy. Based on this model, clinicians can identify patients that are unlikely to respond immunotherapy.

Background: D-3-phosphoglycerate dehydrogenase (PHGDH), which encodes the first enzyme in serine biosynthesis, is overexpressed in human cancers and has been proposed as a drug target. However, whether PHGDH is critical for the proliferation or homeostasis of tissues following the postnatal period is unknown. Methods: To study PHGDH inhibition in adult animals, we developed a knock-in mouse model harboring a PHGDH shRNA under the control of a doxycycline-inducible promoter. With this model, PHGDH depletion can be globally induced in adult animals, while sparing the brain due to poor doxycycline delivery. Results: We found that PHGDH depletion is well tolerated, and no overt phenotypes were observed in multiple highly proliferative cell compartments. Further, despite detectable knockdown and impaired serine synthesis, liver and pancreatic functions were normal. Interestingly, diminished PHGDH expression reduced liver serine and ceramide levels without increasing the levels of deoxysphingolipids. Further, liver triacylglycerol profiles were altered, with an accumulation of longer chain, polyunsaturated tails upon PHGDH knockdown. Conclusions: These results suggest that dietary serine is adequate to support the function of healthy, adult murine tissues, but PHGDH-derived serine supports liver ceramide synthesis and sustains general lipid homeostasis.

9567 Background: Histone deacetylase inhibitors may enhance tumor immunogenicity through various mechanisms including induced expression of T cell chemokines. A previous phase I trial demonstrated the combination of pembrolizumab (P) with vorinostat (V) in mNSCLC was well tolerated with signals of activity in ICI-pretreated pts. We initiated a randomized trial in the first-line setting with the primary objective to determine if the combination had superior ORR compared to pembrolizumab monotherapy. Methods: Pts with treatment-naïve mNSCLC and PD-L1 expression ≥ 1% were eligible. Pts were randomized open-label 1:1 to receive P 200 mg IV q3 wk as monotherapy [Arm A] or P 200 mg IV q3 wk plus V 400 mg PO daily [Arm B]. The primary endpoint was overall response rate (ORR). Secondary endpoints included DOR, PFS and OS. Tumor biopsies were collected both pre- and on-treatment (day 15-21) for analysis of CD8+ TIL, scored using a 0-3 scale in tumor beds. Here we report results after a preplanned interim analysis for efficacy, with accrual ongoing to a planned total of 39 patients per arm. Results: Between 7/2017 – 1/2019, 49 pts were enrolled, with 47 pts evaluable for response (24 in Arm A and 23 in Arm B). Median age was 69 (range 47 - 87), 49% female, ECOG PS 0/1 in 11%/89%. PD-L1 TPS was ≥50% in 13/24 (54%) of pts in Arm A, and in 13/23 (57%) of pts in Arm B. The most common TRAEs in Arm A included diarrhea (13%), fatigue (8%), and pruritus (8%). 3 pts in Arm A experienced grade ≥ 3 irAEs (including 1 each of grade 3 hepatitis, pneumonitis, and rash). The most common TRAEs in Arm B included anorexia (43%), fatigue (43%), nausea (35%) and increased creatinine (35%). 1 pt in Arm B experienced grade ≥ 3 irAE (1 grade 3 pneumonitis). Pre-treatment CD8+ TIL were not significantly different between Arm A and Arm B (p = 0.85) with the majority of tumors in both arms having a low TIL score of 1 (65% Arm A and 73.7% Arm B). A significant increase from pre-treatment to on-treatment TIL scores was seen in both Arm A (p = 0.001) and Arm B (p = 0.002). The ORR in Arm B pts with low pre-treatment TIL (score = 1) pts was substantially higher (66.7%) than in Arm A (33.3%), suggesting the combination may be especially beneficial against low TIL tumors. Conclusions: The combination arm had a considerably higher ORR compared to pembrolizumab monotherapy, with a manageable toxicity profile. The combination of pembrolizumab plus vorinostat in mNSCLC warrants further investigation. Clinical trial information: NCT02638090 . [Table: see text]