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The addition of nivolumab (anti–PD-1) to ipilimumab (anti–CTLA-4) did not further improve response rate or progression-free survival among patients with PD-L1–positive tumors. The combination was much more effective in patients with PD-L1–negative tumors. Considerable progress in the treatment of metastatic melanoma has been made in the past 5 years, with the approval of immune checkpoint–blocking antibodies and, in parallel, agents targeting aberrant signaling in the 40 to 50% of melanomas with BRAF mutations. 1 – 6 Ipilimumab, an anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, acts to up-regulate antitumor immunity and was the first agent to be associated with an improvement in overall survival in a phase 3 study involving patients with metastatic melanoma. 5 , 6 Ipilimumab was associated with responses in 10% and 15% of patients 5 , 6 ; approximately 20% of treated patients had long-term survival. . . .

The addition of a MEK inhibitor to a BRAF inhibitor improved response rates by nearly 16 percentage points (from 51% to 67%) and improved progression-free survival by 0.5 months (from 8.8 to 9.3 months). Targeted inhibition of the RAF–MEK–ERK (MAPK) pathway with BRAF inhibitors dabrafenib or vemurafenib, as compared with chemotherapy, improves the progression-free and overall survival of patients who have metastatic melanoma with BRAF V600 mutations. 1 , 2 However, resistance develops in a majority of patients, resulting in a median progression-free survival of 6 to 7 months. 3 , 4 Most reported resistance mechanisms reactivate the MAPK pathway. 5 – 7 In addition, BRAF-inhibitor–induced paradoxical activation of the MAPK pathway 8 – 10 can result in secondary cancers, including cutaneous squamous-cell carcinoma, and may reactivate RAS-mutant tumors. 11 – 13 Independently, single-agent trametinib, a MEK inhibitor, improves the overall survival of patients . . .

Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates of the disease differ widely across the globe depending on access to early detection and primary care. Once melanoma has spread, this type of cancer rapidly becomes life-threatening. For more than 40 years, few treatment options were available, and clinical trials during that time were all unsuccessful. Over the past 10 years, increased biological understanding and access to innovative therapeutic substances have transformed advanced melanoma into a new oncological model for treating solid cancers. Treatments that target B-Raf proto-oncogene serine/threonine-kinase (BRAF)V600 (Val600) mutations using selected BRAF inhibitors combined with mitogen-activated protein kinase inhibitors have significantly improved response and overall survival. Furthermore, advanced cutaneous melanoma has developed into a prototype for testing checkpoint-modulating agents, which has increased hope for long-term tumour containment and a potential cure. These expectations have been sustained by clinical success with targeted agents and antibodies that block programmed cell-death protein 1 in locoregional disease, which induces prolongation of relapse-free, distant-metastasis-free, and overall survival times.

With a 5-year minimum follow-up in patients with metastatic melanoma, overall survival at 5 years was 52% with a combination of nivolumab plus ipilimumab, as compared with 44% with nivolumab alone and 26% with ipilimumab alone. Programmed cell death ligand 1 expression did not influence the response rate or progression-free survival.

In long-term follow-up of more than 500 patients with melanoma containing a BRAF V600E or V600K mutation, a combination of dabrafenib plus trametinib was associated with progression-free survival in 19% of the patients and overall survival in 34% at 5 years. A complete response to dabrafenib plus trametinib was the strongest predictor of long-term survival.

Both nivolumab alone and nivolumab plus ipilimumab resulted in longer overall survival among patients with previously untreated advanced melanoma than ipilimumab alone. The combination was associated with a higher rate of toxic effects.

At 5 years of follow-up, the 12-month use of adjuvant therapy with dabrafenib (a BRAF inhibitor) plus trametinib (a MEK inhibitor) in patients with stage III melanoma with BRAF V600 mutations resulted in relapse-free survival of 52%, as compared with 36% with placebo.

In patients with surgically resected melanoma, those with BRAF mutations who received 1 year of oral adjuvant therapy with dabrafenib and trametinib had a 53% lower risk of 3-year recurrence than those who received placebo.

Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers 1 . Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota 2 , 3 . Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8 + T cells and CD20 + B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8 + CD20 + tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7 + naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy. The co-occurrence of tumour-associated CD8 + T cells and CD20 + B cells, and the formation of tertiary lymphoid structures, are linked with improved survival in cohorts of patients with metastatic melanoma.

Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16 Ink4a /p19 Arf ( Cdkn2a ) or p21 Cip1 ( Cdkn1a ) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication. The growth of cancer cells can be stably arrested by cytokine-induced senescence. Here, the authors show that cancers with defects in senescence-inducing cell cycle regulator pathways are resistant to immune checkpoint blockade.