patient-derived tumor cell lines; I.K.Z. and J.M.R. generated and provided cells from an ovarian cancer PDX model; P.B. provided CLL samples for analysis. W.Z. provided expert technical assistance. T.E. generated RNA-seq data for mono-allelic cell lines; T.O. and T.L. generated and quantified Ribo-seq data.

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Highlights d Distinct CD8 + T cell phenotypes are enriched after immune checkpoint blockade (ICB) d Immune checkpoint ligands are upregulated in macrophages and tumor cells after ICB d Two cancer cell subpopulations are conserved across heterogeneous RCC tumors d Cancer cell programs drive distinct immune interactions and predict patient outcomes

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Nivolumab, an immune checkpoint inhibitor (ICI) targeting the programmed death-1 (PD-1) pathway, is approved for metastatic clear cell renal cell carcinoma (ccRCC). 1 Loss-of-function (truncating) mutations in PBRM1, a PBAF-complex gene commonly mutated in ccRCC, were previously associated with clinical benefit from anti-PD-1 therapy in a smaller study, 2 Herein, this association was examined in an independent cohort from a randomized clinical trial 1 to determine whether PBRM1 alterations are a marker of response to ICI treatment.Methods | Archival tumor tissue (collected before antiangiogenic therapy) was obtained from patients enrolled in a randomized, phase 3 trial that demonstrated improved overall survival (OS) with nivolumab vs everolimus in patients with ccRCC who received prior antiangiogenic therapy. 1 This study was conducted under a secondary use protocol, approved by the Dana-Farber Cancer Institute. Written informed consent was obtained from participants. This post hoc analysis included 382 of 803 patients who were consented for genomic studies and passed quality control. 2 This cohort was not significantly different from the other 421 patients in response or progressionfree survival (PFS). Putative truncating mutations (frameshift insertion/deletion, nonsense, splice-site) 2 in PBRM1 were manually reviewed using the Integrative Genomics Viewer. 3

The management of advanced renal cell carcinoma (RCC) has been transformed by the development of immune checkpoint inhibitors (ICIs), but still most RCC patients do not receive durable clinical benefit. Importantly, RCC differs substantially from other immunotherapyresponsive solid tumors -it has a modest mutation burden, and paradoxically, high CD8 + T cell infiltration has been associated with a worse prognosis. Building on the successes of inhibitory antibodies targeting the PD-1 and CTLA-4 axes, multiple innovative immunotherapies are now in clinical development for the treatment of RCC, including new ICIs, co-stimulatory pathway agonists, modified cytokines, metabolic pathway modulators, cellular therapies, and therapeutic vaccinations. However, the successful development of such novel immune-based treatments and of immunotherapy-based combinations will require a RCC-specific framework for understanding the necessary immunotherapeutic interventions that underlie an effective anti-tumor immune response. Here, using the structure provided by the well-described cancer-immunity cycle, we outline the key steps required for a successful anti-RCC immune response, and describe the development of promising new immunotherapies within the context of this framework. With this approach, we summarize and analyze encouraging targets within the RCC microenvironment, and review the landscape of antigen-directed therapies in this disease.

Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase   (IDO/TDO) inhibitors.

Background: Interleukin-6 and interleukin-10 both activate the same signaling mediator, STAT3, yet generate nearly opposing responses. Results: Interleukin-6 and interleukin-10 signaling lead to different durations of STAT3 activation and consequently distinct responses. Conclusion:The duration of receptor and STAT3 activation determines the specific cytokine response. Significance: This work reveals a signaling coding mechanism that relieves a cellular information bottleneck.