To better understand intrinsic resistance to immune checkpoint blockade (ICB), we established a comprehensive view of the cellular architecture of the treatment-naive melanoma ecosystem and studied its evolution under ICB. Using single-cell, spatial multi-omics, we showed that the tumor microenvironment promotes the emergence of a complex melanoma transcriptomic landscape. Melanoma cells harboring a mesenchymal-like (MES) state, a population known to confer resistance to targeted therapy, were significantly enriched in early on-treatment biopsies from non-responders to ICB. TCF4 serves as the hub of this landscape by being a master regulator of the MES signature and a suppressor of the melanocytic and antigen presentation transcriptional programs. Targeting TCF4 genetically or pharmacologically, using a bromodomain inhibitor, increased immunogenicity and sensitivity of MES cells to ICB and targeted therapy. We thereby uncovered a TCF4-dependent regulatory network that orchestrates multiple transcriptional programs and contributes to resistance to both targeted therapy and ICB in melanoma.

The primary analysis of the phase 3 ALCANZA trial showed significantly improved objective responses lasting ≥4 months (ORR4; primary endpoint) and progression-free survival (PFS) with brentuximab vedotin vs physician’s choice (methotrexate or bexarotene) in CD30-expressing mycosis fungoides (MF) or primary cutaneous anaplastic large-cell lymphoma (C-ALCL). Cutaneous T-cell lymphomas often cause pruritus and pain; brentuximab vedotin improved skin symptom burden with no negative effects on quality of life. We report final data from ALCANZA (median follow-up, 45.9 months). Adults with previously treated CD30-expressing MF/C-ALCL were randomly assigned to brentuximab vedotin (n = 64) or physician’s choice (n = 64). Final data demonstrated improved responses per independent review facility with brentuximab vedotin vs physician’s choice: ORR4; 54.7% vs 12.5% (P < .001); complete response, 17.2% vs 1.6% (P = .002). Median PFS with brentuximab vedotin vs physician’s choice was 16.7 months vs 3.5 months (P < .001). Median time to the next treatment was significantly longer with brentuximab vedotin than with physician’s choice (14.2 vs 5.6 months; hazard ratio, 0.27; 95% confidence interval, 0.17-0.42; P < .001). Of 44 patients in the brentuximab vedotin arm who experienced any-grade peripheral neuropathy, (grade 3, n = 6; grade 4, n = 0), 86% (38 of 44) had complete resolution (26 of 44) or improvement to grades 1 and 2 (12 of 44). Peripheral neuropathy was ongoing in 18 patients (all grades 1-2). These final analyses confirm improved, clinically meaningful, durable responses and longer PFS with brentuximab vedotin vs physician’s choice in CD30-expressing MF or C-ALCL. This trial was registered at https://www.clinicaltrials.gov as #NCT01578499.

PURPOSE: In rare cases, immune checkpoint inhibitors (ICIs) cause immune-mediated myocarditis. However, true incidence of other major adverse cardiovascular events (MACEs) after ICI treatment remains unknown, mainly because late occurring side effects are rarely reported in prospective clinical trials. The aims of this study were (1) to identify incidence and risk factors of MACE in a real-life ICI-treated cancer cohort and (2) to compare incidence rates with patients with cancer who are not treated with ICIs and population controls. METHODS: In total, 672 patients treated with ICIs were included. The primary end point was MACE, a composite of acute coronary syndrome, heart failure (HF), stroke, and transient ischemic attack. Secondary outcomes were acute coronary syndrome and HF separately. Incidence rates were compared between groups after matching according to age, sex, cardiovascular history, and cancer type. RESULTS: The incidence of MACE was 10.3% during a median follow-up of 13 (interquartile range, 6-22) months. In multivariable analysis, a history of HF (hazard ratio 2.27; 95% CI, 1.03 to 5.04; P = .043) and valvular heart disease (hazard ratio 3.01; 95% CI, 1.05 to 8.66; P = .041) remained significantly associated with MACE. Cumulative incidence rates were significantly higher in the ICI group compared with the cancer cohort not exposed to ICI and the population controls, mainly driven by a higher risk of HF events. CONCLUSION: Cardiovascular events during and after ICI treatment are more common than currently appreciated. Patients at risk are those with a history of cardiovascular disease. Compared with matched cancer and population controls, MACE incidence rates are significantly higher, suggesting a potential harmful effect of ICI treatment besides the underlying risk.

Clinically relevant immunological biomarkers that discriminate between diverse hypofunctional states of tumor-associated CD8 ⁺ T cells remain disputed. Using multiomics analysis of CD8 ⁺ T cell features across multiple patient cohorts and tumor types, we identified tumor niche–dependent exhausted and other types of hypofunctional CD8 ⁺ T cell states. CD8 ⁺ T cells in “supportive” niches, like melanoma or lung cancer, exhibited features of tumor reactivity–driven exhaustion (CD8 ⁺ T _EX ). These included a proficient effector memory phenotype, an expanded T cell receptor (TCR) repertoire linked to effector exhaustion signaling, and a cancer-relevant T cell–activating immunopeptidome composed of largely shared cancer antigens or neoantigens. In contrast, “nonsupportive” niches, like glioblastoma, were enriched for features of hypofunctionality distinct from canonical exhaustion. This included immature or insufficiently activated T cell states, high wound healing signatures, nonexpanded TCR repertoires linked to anti-inflammatory signaling, high T cell–recognizable self-epitopes, and an antiproliferative state linked to stress or prodeath responses. In situ spatial mapping of glioblastoma highlighted the prevalence of dysfunctional CD4 ⁺ :CD8 ⁺ T cell interactions, whereas ex vivo single-cell secretome mapping of glioblastoma CD8 ⁺ T cells confirmed negligible effector functionality and a promyeloid, wound healing–like chemokine profile. Within immuno-oncology clinical trials, anti–programmed cell death protein 1 (PD-1) immunotherapy facilitated glioblastoma’s tolerogenic disparities, whereas dendritic cell (DC) vaccines partly corrected them. Accordingly, recipients of a DC vaccine for glioblastoma had high effector memory CD8 ⁺ T cells and evidence of antigen-specific immunity. Collectively, we provide an atlas for assessing different CD8 ⁺ T cell hypofunctional states in immunogenic versus nonimmunogenic cancers.