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Melanoma, with increasing annual incidence worldwide, is one of the deadliest cutaneous malignancies often treated with immunotherapy, which has led to commonly encountered immune-related adverse events (irAEs) including bullous pemphigoid (BP). The relation between an individual's HLA inheritance and risk in development of BP is well studied. The development of BP as an irAE in melanoma patients receiving immunotherapy is also well reported and considered to be related to the expression of BP180 in malignant melanoma. In presented work, the association of enriched presence of certain HLA alleles and haplotypes that increase risk of developing BP as an irAE has been investigated in seven cutaneous cancer patients who presented with immunotherapy-associated BP, diagnosed by skin biopsy and positive serology for anti-BP 180 autoantibody. Their HLA typing revealed an enriched presence of certain BP-related HLA alleles, and haplotypes, particularly HLA-DQB1*03:01, which was present in all seven patients, whilst its occurrence in the general population is very low. Additionally, some patients had more than one and in a few patients had the whole haplotype of BP related HLA. Not only can such enriched presence be considered a role in risk stratification to initiate or continue immunotherapy, but it may shed a light to existing disease genotypes that can become unmasked to phenotypic clinically presenting BP due to immunotherapy rather than just a random AE., (© 2024 The Author(s). International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy with the aggressive cSCC subtype being especially worrisome due to its higher metastatic and mortality rate. An 80-year-old immunocompetent Caucasian man presented with a locally advanced and recurrent cSCC for which he underwent six Mohs surgeries, radiation therapy, and standard immunotherapy treatments. Throughout treatment, the patient's cancer continued to progress across different regions of the face. Biopsy and analysis were performed and showed that the cSCCs had a high mutational burden and oncogenes known to be present in tumors with aggressive nature. After the algorithmically applied standard of care failed to cure or control the progressing disease, the genetic analysis favored dostarlimab as a suitable option. With only three doses of 500 mg dostarlimab q3 weeks, the patient showed a fast response with macroscopic resolution of clinically discernible disease of, the previously noted, locally advanced cSCC on his right forehead, as well as other primary keratinocyte carcinomas on his left contralateral face, nose, left leg, and neck. This remarkable case can present an option for complex patients with locally advanced and recurrent cSCC who failed the current standard of care. Moreover, it warrants a proper clinical trial to assess efficacy and potential indication of dostarlimab in such patients. Of note is the presence of a KMT2D mutation and its well-identified correlation with mismatch repair deficiency (dMMR) and poor prognosis, which can play an informative role in clinical decision making and precision therapeutic choice at the point of care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gandarillas, Tang and Dasgeb.)

Background: The success of immunotherapy has made it a lifesaving treatment, but not without side effects. Currently, the risk factors for developing immune-related adverse events (irAEs) in patients who receive immunotherapy are poorly understood, and there is no risk-stratifying mechanism for potentially fatal irAEs. It is postulated that oncology patients with preexisting autoimmune diseases are likely to have flares on immunotherapy. However, some patients develop de novo autoimmune conditions on immunotherapy without a prior history. Literature reports have postulated that human leukocyte antigen (HLA) inherence may play a role in irAEs. However, this potential remains underexplored., Methods: The oncology patients who developed autoimmune adverse events on immunotherapy for whom the continuation of treatment was prudent or lifesaving were selected. Of note, all nine patients received checkpoint inhibitors (CIs). Of the nine selected patients, only one had a prior history of an autoimmune condition. None of the nine selected patients had an active autoimmune condition at the time of CI initiation. Their HLA was typed, and the results were cross-referenced with the literature reports in PubMed and Google search with the corresponding autoimmune condition of each patient., Results: Herein, we report nine patients with irAEs for whom retrospective HLA typing revealed the inherence of multiple related HLA alleles that may correspond to the autoimmune condition that they had developed on immunotherapy. It is to be mentioned that the inherence of enriched disease-related HLA alleles was shared among patients with the same irAEs. These patients developed a range of irAEs including bullous pemphigoid, pemphigus foliaceus/vulgaris, thyroiditis, vitiligo, and hepatitis on immunotherapy. Although some combinations of disease-related HLA were well reported in otherwise idiopathic autoimmune diseases, a frequently repeated HLA allele combination in our patient population was found to be rarely seen in the general population., Conclusion: The authors suggest that an enriched inherence of disease-related HLA alleles may play a role in the genetic propensity for the development of irAEs in oncology patients, who receive immunotherapy, including CIs. Inherence of more than one or a cluster of particular autoimmune disease-related HLA alleles in patients who receive immunotherapy may unmask the corresponding autoimmune disease as the genotype inherence presents with the phenotype of the corresponding condition. It is suggested that enriched linked HLA genotypes, which are otherwise rare in the general population, may present as the corresponding phenotype of the autoimmune condition. Such clinical presentation, enhanced by immunotherapy, such as CIs, can play a role in risk stratifying patients for precision medicine and improve the outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gandarillas, Newland, Toppmeyer, Stephenson, Denzin and Dasgeb.)

The cytoskeleton and cell-matrix adhesions constitute a dynamic network that controls cellular behavior during development and cancer. The Focal Adhesion Kinase (FAK) is a central actor of these cell dynamics, promoting cell-matrix adhesion turnover and active membrane fluctuations. However, the initial steps leading to FAK activation and subsequent promotion of cell dynamics remain elusive. Here, we report that the serine/threonine kinase PKCθ participates in the initial steps of FAK activation. PKCθ, which is strongly expressed in aggressive human breast cancers, controls the dynamics of cell-matrix adhesions and active protrusions through direct FAK activation, thereby promoting cell invasion and lung metastases. Using various tools for in vitro and live cell studies, we precisely decipher the molecular mechanisms of FAK activation. PKCθ directly interacts with the FAK FERM domain to open FAK conformation through PKCθ's specific V3 domain, while phosphorylating FAK at newly identified serine/threonine residues within nascent adhesions, inducing cell dynamics and aggressive behavior. This study thus places PKCθ-directed FAK opening and phosphorylations as an original mechanism controlling dynamic, migratory, and invasive abilities of aggressive breast cancer cells, further strengthening the emerging oncogenic function of PKCθ., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Relapses driven by chemoresistant leukemic cell populations are the main cause of mortality for patients with acute myeloid leukemia (AML). Here, we show that the ectonucleotidase CD39 (ENTPD1) is upregulated in cytarabine-resistant leukemic cells from both AML cell lines and patient samples in vivo and in vitro . CD39 cell-surface expression and activity is increased in patients with AML upon chemotherapy compared with diagnosis, and enrichment in CD39-expressing blasts is a marker of adverse prognosis in the clinics. High CD39 activity promotes cytarabine resistance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated adaptive mitochondrial stress response. Finally, genetic and pharmacologic inhibition of CD39 ecto-ATPase activity blocks the mitochondrial reprogramming triggered by cytarabine treatment and markedly enhances its cytotoxicity in AML cells in vitro and in vivo . Together, these results reveal CD39 as a new residual disease marker and a promising therapeutic target to improve chemotherapy response in AML. SIGNIFICANCE: Extracellular ATP and CD39-P2RY13-cAMP-OxPHOS axis are key regulators of cytarabine resistance, offering a new promising therapeutic strategy in AML. This article is highlighted in the In This Issue feature, p. 1426 ., (©2020 American Association for Cancer Research.)

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphomas are tumors that carry translocations involving the ALK gene at the 2p23 locus, leading to the expression of ALK tyrosine kinase fusion oncoproteins. Amongst hematologic malignancies, these lymphomas are particular in that they express very low levels of B-cell lymphoma 2 (BCL2), a recognized inhibitor of apoptosis and autophagy, two processes that share complex interconnections. We have previously shown that treatment of ALK-positive anaplastic large cell lymphoma cells with the ALK tyrosine kinase inhibitor crizotinib induces autophagy as a pro-survival response. Here, we observed that crizotinib-mediated inactivation of ALK caused an increase in BCL2 levels that restrained the cytotoxic effects of the drug. BCL2 downregulation in combination with crizotinib treatment potentiated loss of cell viability through both an increase in autophagic flux and cell death, including apoptosis. More importantly, our data revealed that the blockade of autophagic flux completely reversed impaired cell viability, which demonstrates that excessive autophagy is associated with cell death. We propose that the downregulation of BCL2 protein, which plays a central role in the autophagic and apoptotic machinery, combined with crizotinib treatment may represent a promising therapeutic alternative to current ALK-positive anaplastic large cell lymphoma treatments., (Copyright© 2019 Ferrata Storti Foundation.)