Faculty Bibliography

Since the original description of CRTC1::TRIM11 fusion cutaneous tumors (CTCT) in 2018, an increasing number of cases with metastatic behavior have been reported, yet there are limited studies analyzing prognostic parameters. This expanding data set presents an opportunity for reappraisal of clinical behavior. We present a series of 21 cases with detailed morphologic, molecular, clinical outcomes, and therapeutic response data. We utilize this data and a meta-analysis of all the cases in the literature to assess potential prognostic parameters to assist in clinical management. Primary tumors resulting in metastasis were larger (P=0.038), had higher mitotic counts (P<0.001), were more frequently ulcerated (P=0.001), and exclusively harbored TERT promoter mutations (P=0.005). A functional analysis of mixed data demonstrated a clear clustering pattern in which metastatic cases had larger diameters and were more mitotically active compared with nonmetastatic cases. Inclusion of TERT promoter mutational status further improved the model. There were no metastatic events among cases meeting all the following criteria: size <1.2 cm, <7 mitoses/mm2, and absent TERT promoter mutation. Metastatic events frequently involved regional lymph nodes, and all patients with distant metastasis had pulmonary involvement. Considering metastatic events in 23% of cases, sentinel lymph node biopsy and imaging studies may be considered in some cases, while, in cases with smaller size, low mitotic counts, and no evidence of a TERT promoter mutation, excision alone may be adequate. Given poor therapeutic responses in reported metastatic cases, more therapeutic options should be explored.

Merkel cell carcinomas (MCC) typically arise from the clonal integration of the Merkel cell polyomavirus. Immunogenic viral oncoproteins then lead to tumorigenesis. Oncoprotein-specific T cells are essential for anti-MCC immunity, but it is unclear whether B cells promote tumor control. In this study, we analyzed the frequency and phenotype of viral oncoprotein-specific and total B cells in blood samples from 47 patients with MCC and tumor samples from another 19 patients with MCC. The phenotype of blood B cells did not correlate with the outcomes of patients with MCC. In contrast, all 11 patients with robust oncoprotein-specific antibody-secreting and/or germinal center B cells in tumors experienced long-term MCC control. In vitro, B cells engineered to be specific for viral oncoproteins increased the sensitivity of oncoprotein-specific CD4+ T cells by more than 50-fold. Together, our findings suggest that cancer-specific B cells promote antitumor immunity via increased responses by T cells and that cancer-specific augmentation of B cells could be therapeutically relevant. See related Spotlight, p. 716.

Lymphatic vessels activate anti-tumor immune surveillance and support metastasis. Whether there are distinct lymphatic phenotypes that govern immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential. We demonstrate that intratumoral lymphatic vessel density negatively correlates with cytotoxic immunity and that IFNγ reprograms the intratumoral lymphatic state. Lymphatic deletion of Ifngr1 expanded the intratumoral lymphatic network and drove the emergence of a tip-like state that promotes lymph node metastasis but not dendritic cell migration or response to immune checkpoint blockade (ICB). Mechanistically, IFNγ restrains proliferation and cell state programs through inhibition of mitochondrial respiration. Lymphatic-specific inhibition of mitochondrial complex III restrained the intratumoral tip-like state, blocked metastasis, and enhanced the response to ICB. Our data reveal that IFNγ induces a metabolic and phenotypic switch in tumor-associated lymphatic vessels that blocks regional metastasis and reinforces immune surveillance.

Atopic diseases associated with allergens, as well as allergic diseases, frequently arise early in life; however, the age-dependent mechanisms governing immune responses to allergens remain poorly understood¹. Here we find that in early life, exposure to common allergens triggers a distinct bifurcated immune response, simultaneously triggering type 17 inflammation in the skin and initiating canonical T helper 2 sensitization in the lymph nodes. This early-life γδ type 17-mediated dermatitis primes the exaggerated allergic lung inflammation upon secondary allergen exposure. Mechanistically, we find dendritic cell (DC)-mediated type 17 activation directly in the skin without requiring migration to lymph nodes; we term this state 'peripheral immune inducer' (pii) DC. CD301b⁺ conventional type 2 DCs acquire allergen, adopt the pii-DC state, produce IL-23 and activate local γδ type 17 cells independently of lymph-node engagement. The pii-DC state is enabled by the immature hypothalamic-pituitary-adrenal axis and physiologically low systemic glucocorticoids characteristic of early life^2,3; DC-specific deletion of the glucocorticoid receptor recapitulates the pii-DC phenotype. These findings define a developmental checkpoint, set by neuroendocrine maturation, that enables in situ DC activation and immune induction, thereby shaping age-dependent responses to allergens.

INTRODUCTION/UNASSIGNED:Immune checkpoint inhibitors have become an increasingly effective treatment for various malignancies, although their use is associated with a range of organ toxicities. As these therapies become more prevalent, it is critical to establish appropriate management and long-term surveillance strategies for patients who develop immune-related adverse events. AREAS COVERED/UNASSIGNED:This review explores the chronic sequelae that may result from immune-related adverse events and focuses specifically on their persistence, outcomes, and implications for future research. A literature review was conducted using PubMed to identify relevant articles from within the last 10 years. EXPERT OPINION/UNASSIGNED:While acute management of irAEs has improved over the past decade, there is a major gap in understanding and addressing their chronic sequelae. Challenges in studying these sequelae include the complexity of cancer care, overlapping clinical presentations, and previously, a lack of long-term data. Continued research from large multicenter studies and dedicated databases can identify high-risk patients, inform risk-benefit discussions, refine management strategies, and pave the way for evidence-based, long-term care.