Joey H. Li

Anaplastic lymphoma kinase (ALK) inhibitors such as alectinib are standard first-line treatments for ALK-positive lung cancers. While alectinib is generally well tolerated and provides excellent disease control, rare reports have suggested renal toxicities associated with alectinib treatment. Here, we report a case of a 60-year-old man with a history of stage IV non-small cell lung cancer who had been receiving alectinib for eight months and presented to the emergency department with anuria, acutely elevated creatinine, and hyperkalemia. Nephrotoxic medications, including alectinib, were suspended in the setting of severe acute kidney injury (AKI). He was started on emergent hemodialysis and treated with corticosteroids, leading to resolution of the kidney injury and electrolyte abnormalities. Renal biopsy revealed mixed acute tubular necrosis and acute interstitial nephritis. This case reinforces the rare association between alectinib and AKI, emphasizing the importance of monitoring for and recognizing signs of nephrotoxicity in patients receiving this therapy, even after months of stable renal function.

DEG Table for Pre vs Post (mRNAseq)

DEG Table for R vs NR (mRNAseq)

Supplementary Figures 1-5 and Supplementary Tables 1-2

Purpose:Determinants of treatment outcomes to chemotherapy-based regimens in metastatic pancreatic ductal adenocarcinoma (PDA) remain ill-defined. Our aim was to examine tissue-based correlates of treatment response and resistance using matched baseline and on-treatment biopsies collected from patients with PDA treated in the first-line metastatic setting.Experimental Design:Patients with treatment-naïve metastatic PDA were enrolled in a Phase II trial (NCT02077881) investigating gemcitabine plus nab-paclitaxel in combination with indoximod, an orally administered small-molecule inhibitor of the IDO pathway. Baseline and on-treatment biopsies (week 8) of metastatic lesions (88% liver) were collected from a cohort of responders (N = 8) and non-responders (N = 8) based on RECIST v1.1 and examined by multiplex IHC and mRNA sequencing.Results:Treatment altered the transcriptional profile of metastatic lesions with a decrease in tumor cell proliferation independent of treatment response. The antiproliferative response was seen in both basal and classical PDA subtypes. PDA subtype was not associated with survival outcomes; instead, genes involved in immune activation distinguished responders from non-responders. Tumor response was associated with an increase in CD3+ and CD8+ T-cell infiltrates into metastatic lesions. A composite of decreased tumor proliferation in response to treatment and increased CD8 T-cell infiltration in metastatic lesions identified responders and associated with a favorable survival outcome.Conclusions:Our findings suggest that inhibiting cancer cell proliferation alone in PDA is insufficient to produce tumor responses and support a role for tumor-extrinsic mechanisms, such as CD8+ T cells, which combine with the cancer cell proliferation index to define treatment outcomes.

Immune cells undergo rapid metabolic reprogramming to fuel effector responses. However, whether the metabolic pathways that supply these functions differ between human and mouse immune cells is poorly understood. Using a comparative metabolomics approach, here we show both conserved and species-distinct metabolite alterations in cytokine-activated primary human and mouse natural killer (NK) cells. Activated human NK cells fail to perform de novo serine synthesis, resulting in broadly impaired effector functions when serine starved ex vivo or during in vivo dietary serine restriction, limiting their antitumour function. In contrast, activated mouse NK cells perform de novo serine synthesis to fuel one-carbon metabolism and proliferation, resulting in increased metabolic flexibility during ex vivo and dietary serine restriction. While NK cells from both species require one-carbon metabolism to proliferate and produce interferon-γ, GCLC-dependent glutathione synthesis tunes cytotoxic versus inflammatory function in human NK cells. Thus, activated NK cell functions display species-specific requirements for serine metabolism, and environmental serine availability dictates activated human NK cell functions.

Natural killer (NK) cells are a critical first line of defense against viral infection. Rare mutations in a small subset of transcription factors can result in decreased NK cell numbers and function in humans, with an associated increased susceptibility to viral infection. However, our understanding of the specific transcription factors governing mature human NK cell function is limited. Here we use a non-viral CRISPR–Cas9 knockout screen targeting genes encoding 31 transcription factors differentially expressed during human NK cell development. We identify myocyte enhancer factor 2C (MEF2C) as a master regulator of human NK cell functionality ex vivo. MEF2C-haploinsufficient patients and mice displayed defects in NK cell development and effector function, with an increased susceptibility to viral infection. Mechanistically, MEF2C was required for an interleukin (IL)-2- and IL-15-mediated increase in lipid content through regulation of sterol regulatory element-binding protein (SREBP) pathways. Supplementation with oleic acid restored MEF2C-deficient and MEF2C-haploinsufficient patient NK cell cytotoxic function. Therefore, MEF2C is a critical orchestrator of NK cell antiviral immunity by regulating SREBP-mediated lipid metabolism.

Purpose:Determinants of treatment outcomes to chemotherapy-based regimens in metastatic pancreatic ductal adenocarcinoma (PDA) remain ill-defined. Our aim was to examine tissue-based correlates of treatment response and resistance using matched baseline and on-treatment biopsies collected from patients with PDA treated in the first-line metastatic setting.Experimental Design:Patients with treatment-naïve metastatic PDA were enrolled in a Phase II trial (NCT02077881) investigating gemcitabine plus nab-paclitaxel in combination with indoximod, an orally administered small-molecule inhibitor of the IDO pathway. Baseline and on-treatment biopsies (week 8) of metastatic lesions (88% liver) were collected from a cohort of responders (N = 8) and non-responders (N = 8) based on RECIST v1.1 and examined by multiplex IHC and mRNA sequencing.Results:Treatment altered the transcriptional profile of metastatic lesions with a decrease in tumor cell proliferation independent of treatment response. The antiproliferative response was seen in both basal and classical PDA subtypes. PDA subtype was not associated with survival outcomes; instead, genes involved in immune activation distinguished responders from non-responders. Tumor response was associated with an increase in CD3+ and CD8+ T-cell infiltrates into metastatic lesions. A composite of decreased tumor proliferation in response to treatment and increased CD8 T-cell infiltration in metastatic lesions identified responders and associated with a favorable survival outcome.Conclusions:Our findings suggest that inhibiting cancer cell proliferation alone in PDA is insufficient to produce tumor responses and support a role for tumor-extrinsic mechanisms, such as CD8+ T cells, which combine with the cancer cell proliferation index to define treatment outcomes.