Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.

Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintuitively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor-infiltrating CD8+ T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and ß-catenin signaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD+, resulting in reduction of SIRT1-mediated ß-catenin deacetylation and enhanced ß-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-ß-catenin axis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNγ-PKM2-ß-catenin cascade underlies ICB-associated HPD.

Anatomical and functional correlates of cystic macular edema in retinitis pigmentosa.

Cystoid macular edema (CME) is a major cause of central visual deterioration in retinitis pigmentosa. The exact reason for CME and its prognostic significance in this patient population is unknown. We seek to find clues to answer these questions by examining the anatomical correlations between retinal cysts and retinal morphometric parameters in a cohort of patients with retinitis pigmentosa and CME. For this reason, 103 patients (196 eyes) with untreated cystoid macular edema (CME) were identified from a pool of 578 genotyped patients with retinitis pigmentosa. Image analyses were conducted using three central horizontal OCT scans of these patients to calculate cross-sectional areas of the retinal nerve fiber layer, outer retinal, inner retinal, cysts, and total retinal areas. Lengths of the ellipsoid zone and outer limiting membrane were also measured. Best-fit curves were derived for analyzing the factors playing a role in the size of the retinal cysts and the patients' visual acuity. Generalized Estimating Equation and multivariate linear regression analyses were conducted to determine the correlations between visual acuity, morphometric and clinical data, and the significant cyst size and visual acuity determinants. Twenty-five percent of the screened patients (103/578) had CME. Patients with autosomal dominant retinitis pigmentosa had the highest incidence of CME (43.6%, p<0.001) but also had the best visual acuity (20/34±20/30, p = 0.02). The total cyst area was 0.14±0.18 mm2. Outer retinal area (B = 0.214; p = 0.008), age (B = -0.003; p<0.001) and retinal nerve fiber area (B = 0.411; p = 0.005) were main determinants of the (r = 0.44; p<0.001) cyst size. Cysts resolved with progressing retinal degeneration. Length of the intact ellipsoid zone (B = -5.16E-5; p<0.001), the inheritance pattern (B = 0.04; p = 0.028) and retinal nerve fiber area (B = 0.751; p<0.001) were the main determinants of visual acuity. In patients with retinitis pigmentosa and cystoid macular edema, retinal nerve fiber layer thickness is associated with decreasing visual acuity and cyst size. This finding suggests that intraretinal cysts may compress retinal axons and cause subsequent visual loss in retinitis pigmentosa.

Overall and COVID-19-specific citation impact of highly visible COVID-19 media experts: bibliometric analysis.

OBJECTIVE: To evaluate whether the COVID-19 experts who appear most frequently in media have high citation impact for their research overall, and for their COVID-19 peer-reviewed publications in particular and to examine the representation of women among such experts. DESIGN: Cross-linking of data sets of most highly visible COVID-19 media experts with citation data on the impact of their published work (career-long publication record and COVID-19-specific work). SETTING: Cable news appearance in prime-time programming or overall media appearances. PARTICIPANTS: Most highly visible COVID-19 media experts in the USA, Switzerland, Greece and Denmark. INTERVENTIONS: None. OUTCOME MEASURES: Citation data from Scopus along with discipline-specific ranks of overall career-long and COVID-19-specific impact based on a previously validated composite citation indicator. RESULTS: We assessed 76 COVID-19 experts who were highly visible in US prime-time cable news, and 50, 12 and 2 highly visible experts in media in Denmark, Greece and Switzerland, respectively. Of those, 23/76, 10/50, 2/12 and 0/2 were among the top 2% of overall citation impact among scientists in the same discipline worldwide. Moreover, 37/76, 15/50, 7/12 and 2/2 had published anything on COVID-19 that was indexed in Scopus as of 30 August 2021. Only 18/76, 6/50, 2/12 and 0/2 of the highly visible COVID-19 media experts were women. 55 scientists in the USA, 5 in Denmark, 64 in Greece and 56 in Switzerland had a higher citation impact for their COVID-19 work than any of the evaluated highly visible media COVID-19 experts in the respective country; 10/55, 2/5, 22/64 and 14/56 of them were women. CONCLUSIONS: Despite notable exceptions, there is a worrisome disconnect between COVID-19 claimed media expertise and scholarship. Highly cited women COVID-19 experts are rarely included among highly visible media experts.

Validation of the American Joint Committee on Cancer Eighth Edition Staging of Patients With Metastatic Cutaneous Melanoma Treated With Immune Checkpoint Inhibitors.

Importance: Immune checkpoint inhibitors (ICIs) have transformed the survival of patients with metastatic melanoma. Patient prognosis is reflected by the American Joint Committee on Cancer (AJCC) staging system; however, it is unknown whether the metastatic (M) stage categories for cutaneous melanoma remain informative of prognosis in patients who have received ICIs. Objectives: To evaluate the outcomes of patients with metastatic cutaneous melanoma based on the M stage category from the AJCC eighth edition and to determine whether these designations continue to inform the prognosis of patients who have received ICIs. Design, Setting, and Participants: This cohort study included patients with metastatic cutaneous melanoma who were treated between August 2006 and August 2019 at the University of Michigan. The estimated median follow-up time was 35.5 months. Patient data were collected via the electronic medical record system. Critical findings were externally validated in a multicenter nationwide cohort of patients treated within the Veterans Affairs health care system. Data analysis was conducted from February 2020 to January 2021. Exposures: All patients were treated with dual-agent concurrent ipilimumab and nivolumab followed by maintenance nivolumab or single-agent ipilimumab, nivolumab, or pembrolizumab therapy. Patients were staged using the AJCC eighth edition. Main Outcomes and Measures: Univariable and multivariable analyses were used to assess the prognostic value of predefined clinicopathologic baseline factors on survival. Results: In a discovery cohort of 357 patients (mean [SD] age, 62.6 [14.2] years; 254 [71.1%] men) with metastatic cutaneous melanoma treated with ICIs, the M category in the AJCC eighth edition showed limited prognostic stratification by both univariable and multivariable analyses. The presence of liver metastases and elevated levels of serum lactate dehydrogenase (LDH) offered superior prognostic separation compared with the M category (liver metastases: hazard ratio, 2.22; 95% CI, 1.48-3.33; P < .001; elevated serum LDH: hazard ratio, 1.73; 95% CI, 1.16-2.58; P = .007). An updated staging system based on these factors was externally validated in a cohort of 652 patients (mean [SD] age, 67.9 [11.6] years; 630 [96.6%] men), with patients without liver metastases or elevated LDH levels having the longest survival (median overall survival, 30.7 months). Conclusions and Relevance: This study found that the AJCC eighth edition M category was poorly reflective of prognosis in patients receiving ICIs. Future staging systems could consider emphasizing the presence of liver metastases and elevated LDH levels. Additional studies are needed to confirm the importance of these and other prognostic biomarkers.

Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.

The impact of BRAF mutation status on clinical outcomes with anti-PD-1 monotherapy versus combination ipilimumab/nivolumab in treatment-naïve advanced stage melanoma.

Nearly half of all metastatic melanoma patients possess the BRAF V600 mutation. Several therapies are approved for advanced stage melanoma, but it is unclear if there is a differential outcome to various immunotherapy regimens based on BRAF mutation status. We retrospectively analyzed a cohort of metastatic or unresectable melanoma patients who were treated with combination ipilimumab/nivolumab (ipi/nivo) or anti-PD-1 monotherapy, nivolumab, or pembrolizumab, as first-line treatment. 235 previously untreated patients were identified in our study. Our univariate analysis showed no statistical difference in progression-free survival (PFS) or overall survival (OS) with ipi/nivo versus anti-PD-1 monotherapy in the BRAF V600 mutant cohort, but there was improved PFS [HR: 0.48, 95% CI, 0.28-0.80] and OS [HR: 0.50, 95% CI, 0.26-0.96] with ipi/nivo compared to anti-PD-1 monotherapy in the BRAF WT group. After adjusting for known prognostic variables in our multivariable analysis, the BRAF WT cohort continued to show PFS and OS benefit with ipi/nivo compared to anti-PD-1 monotherapy. Our single-institution analysis suggests ipi/nivo should be considered over anti-PD-1 monotherapy as the initial immunotherapy regimen for metastatic melanoma patients regardless of BRAF mutation status, but possibly with greater benefit in BRAF WT.