Search

Tissue-resident memory T cells (TRM) provide frontline protection against pathogens and emerging malignancies. Tumor-infiltrating lymphocytes (TIL) with TRM features are associated with improved clinical outcomes. However, the cellular interactions that program TRM differentiation and function are not well understood. Using murine genetic models and targeted spatial transcriptomics, we found that the CD8+ T cell-derived chemokine XCL1 is critical for TRM formation and conventional DC1 (cDC1) supported the positioning of intestinal CD8+ T cells during acute viral infection. In tumors, enforced Xcl1 expression by antigen-specific CD8+ T cells promoted intratumoral cDC1 accumulation and T cell persistence, leading to improved overall survival. Notably, analysis of human TIL and TRM revealed conserved expression of XCL1 and XCL2. Thus, we have shown that the XCL1-XCR1 axis plays a non-cell autonomous role in guiding intestinal CD8+ TRM spatial differentiation and tumor control., (© 2025 Ferry et al.)

We report the basal cell cancer (BCC) cohort of the SWOG/NCI 1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART), a phase II prospective, multicenter basket trial of nivolumab and ipilimumab. The primary endpoint was objective response rate (ORR) (RECIST v1.1). Overall survival (OS), progression-free survival (PFS), and toxicity were secondary endpoints. Sixteen patients with advanced/metastatic BCC were evaluable. The ORR was 31% (95% CI, 19-50%), and the 12-month OS, 75% (95% CI, 57-100%). Median PFS was 9.3 months (95% CI, 3.3-NA). Of 15 patients evaluable for clinical benefit, five partial responses (PRs) and five stable disease >6 months (total = 10/15 (66.7%)) were seen. The most common toxicities included fatigue (37.5%), pruritis (31.3%), and diarrhea (25%). In patients with advanced/metastatic BCC, ipilimumab and nivolumab produced an ORR of 31% and prolonged (>6 months) PFS in 73% of patients, with seven PFS/iPFS of >1 year, including one with prior anti-PD-1. ClinicalTrials.gov ID: NCT02834013 (Registered 7/15/2016; https://clinicaltrials.gov/ct2/show/NCT02834013 )., Competing Interests: Competing interests: Kurzrock has research funding from Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta, and OmniSeq, as well as consultant fees from LOXO, X-Biotech, Actuate Therapeutics, Roche and NeoMed. She serves as an advisor to Soluventis. She receives speaker fees from Roche and also has equity in IDbyDNA, CureMatch, Inc., and Soluventis. Patel reports grants from Bristol-Myers Squibb, personal fees from Bristol-Myers Squibb, during the conduct of the study; grants from Eli Lilly, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery. Fate Therapeutics, Genocea, Iovance, personal fees from AstraZeneca, Illumina, Tempus, Novartis, outside the submitted work. Chae reports research grants from Abbvie, BMS, Biodesix, Lexent Bio, Freenome; Honoraria/Advisory Boards from Roche/Genentech, AstraZeneca, Foundation Medicine, Counsyl, Guardant Health, Boehringer Ingelheim, Biodesix, Immuneoncia, Lilly Oncology, Merck, and Takeda. During conduct of the trial, Sharon was a full-time employee of the National Cancer Institute (NCI), an arm of the United States government. He reports participation on Advisory Board for Mallinckrodt Pharmaceuticals. Othus reports consulting fees from Merck and Biosight. She serves participant on a Data Safety Monitoring Board or Advisory Board for BMS (Celgene), Grifols, and Glycomimetics. Lao reports research funding during this period from BMS, Genentech, and Dynavax. Ryan reported research support to institution from Bristol-Myers Squibb, Daiichi Sankyo Company, Genentech, Deciphera Pharmaceuticals, Exelixis, Karyopharm Therapeutics, Merck, Pfizer, Xynomic, PTC Therapeutics, NiKang Therapeutics, Shasqi, PF Argentum IP Holdings LLC, Novartis, Rain Therapeutics, IO Biotech, Seagen, Boehringer Ingelheim, and ALX Oncology. He reports providing expert testimony for Pfizer, GlaxoSmithKline, and Boehringer Ingelheim. Schokrpur reports consulting/advisory board fees from OncoHost. Blanke, Chen, Powers, Victor, Shin, Onitilo, and Takebe have no COI disclosures to report; McLeod, Cano-Linson, and Thelkel have no COI disclosures to report. The NCI negotiated a collaborative research and development agreement (CRADA) with Bristol-Myers Squibb to provide nivolumab and ipilimumab for this clinical trial., (© 2025. The Author(s).)

Solid cancers often progress via metastasis to lymph nodes. Consequently, lymphadenectomy is central to stage cancers and eradicates disease spread. However, mounting evidence suggests that cancer immunotherapies drive antitumor immune responses within lymph nodes. This implies that immunotherapy, delivered with standard oncologic therapies, may require specific treatment sequencing to initiate immunosurveillance and affect primary tumor responses. As supported by recent preclinical and clinical studies, lymphatic-preserving strategies may offer the best promise for driving the next generation of breakthrough immunotherapy approaches., Competing Interests: Declaration of interests J.S.G. reports consulting fees from Domain Pharmaceuticals, Pangea Therapeutics, and io9 and is the founder of Kadima Pharmaceuticals, all unrelated to the current study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The role of immunotherapy in the care of surgical oncology patients promises to expand as investigators and clinicians evaluate new targets and approaches. Currently active clinical trials evaluate new immune checkpoints, including lymphocyte activation gene 3, T cell immunoreceptor with Ig and ITIM domains, and killer Ig-like receptor 2DL1/2L3. Vaccines delivered through mRNA have demonstrated exciting results in early clinical trials and hold promise for expanded application. Investigational approaches include dendritic cell vaccines, peptide vaccines, cytokines therapies, and cellular therapies. These studies have the potential to revolutionize the management of surgical oncology patients and promote durable cures following surgical resection., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL + ) cells. Renal tumors with either VHL + or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL + cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL - ) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor., (© 2023. The Author(s).)

Introduction: Approximately 10% of EGFR mutations (EGFRmuts) are uncommon (ucEGFRmuts). We aimed to collect real-world data about osimertinib for patients with ucEGFRmuts., Methods: This is a multicenter, retrospective study of ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC treated with osimertinib as first EGFR inhibitor. The Response Evaluation Criteria in Solid Tumors and response assessment in neuro-oncology brain metastases brain objective response rate (ORR) were evaluated by the investigators. Median progression-free survival (mPFS), median overall survival, and median duration of response (mDOR) were calculated from osimertinib initiation. Mutations found at resistance were collected., Results: A total of 60 patients were included (22 centers, nine countries), with median age of 64 years, 75% females, and 83% Caucasian. The largest subgroups were G719X (30%), L861Q (20%), and de novo Thr790Met (T790M) (15%). The ORR was 61%, mPFS 9.5 months, mDOR 17.4 months, and median overall survival 24.5 months. Regarding patients with no concurrent common mutations or T790M (group A, n = 44), ORR was 60%, mPFS 8.6 months, and mDOR 11 months. For G719X, ORR was 47%, mPFS 8.8 months, and mDOR 9.1 months. For L861Q, ORR was 80%, mPFS 16 months, and mDOR 16 months. For de novo T790M, ORR was 44%, mPFS 12.7 months, and mDOR 46.2 months. Compound EGFRmut including common mutations had better outcome compared with only ucEGFRmut. For 13 patients with a response assessment in neuro-oncology brain metastases-evaluable brain metastases, brain ORR was 46%. For 14 patients, rebiopsy results were analyzed: four patients with additional EGFR mutation (C797S, D585Y, E709K), three with new TP53 mutation, one with c-Met amplification, one with PIK3CA mutation, and one with neuroendocrine transformation., Conclusions: Osimertinib was found to have an activity in ucEGFRmut with a high rate of disease control systemically and intracranially. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest data set of its kind., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: There is a paucity of data on immune checkpoint inhibitors (ICIs) plus doublet chemotherapy (C) in patients with advanced lung cancer whose tumor harbors an actionable mutation. We sought to provide insight into the role of this combination in relation to chemotherapy alone in this patient population., Methods: We conducted a retrospective study at the five University of California National Cancer Institute-designated Comprehensive Cancer Centers. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and significant adverse events. Adverse events in patients who received a tyrosine kinase inhibitor (TKI) post-ICI were also captured., Results: A total of 246 patients were identified, 170 treated with C plus ICI and 76 treated with C alone. Driver alterations included EGFR (54.9%), KRAS (32.9%), ALK (5.3%), HER2 / ERBB2 (2.9%), ROS1 (1.2%), MET (1.2%), RET (0.8%), and BRAF non-V600 (0.8%). The overall PFS and OS hazard ratios were not significant at 1.12 (95% confidence interval 0.83-1.51; p  = 0.472) and 0.86 (95% confidence interval: 0.60-1.24, p  = 0.429), respectively. No significant differences in PFS or OS were observed in the mutational subgroups. Grade 3 or greater adverse events were lower in the C plus ICI group. The multivariate analysis for PFS and OS revealed a performance status (Eastern Cooperative Oncology Group) score of 2, and previous TKI treatment was associated with poorer outcomes with C plus ICI., Conclusions: Our study suggests that patients with oncogenic-driven NSCLC, primarily those with EGFR -driven tumors, treated with a TKI should not subsequently receive C plus ICI. Analysis from prospective clinical trials will provide additional information on the role of ICIs in this group of patients., (© 2022 The Authors.)

Abstract: Work over the past several decades has identified that aberrations in the ErbB signaling pathways are key drivers of oncogenesis, and concurrent efforts to discover targetable vulnerabilities to counter this aberrant oncogenic signaling offer tremendous promise in treating a host of human cancers. These efforts have been centered primarily on EGFR (also known as HER1), leading to the discovery of the first targeted therapies approved for head and neck cancer. More recently, HER2 and HER3 signaling pathways have been identified as highly dysregulated in head and neck cancer. This review highlights the HER2 and HER3 signaling pathways and clinical efforts to target these receptors and their aberrant signaling to treat head and neck squamous cell carcinomas and other head and neck malignancies, including salivary gland carcinomas. This includes the use of small molecule inhibitors and blocking antibodies, both as single agents or as part of multimodal precision targeted and immunotherapies., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Despite the promise of immune checkpoint inhibition (ICI), therapeutic responses remain limited. This raises the possibility that standard of care treatments delivered in concert may compromise the tumor response. To address this, we employ tobacco-signature head and neck squamous cell carcinoma murine models in which we map tumor-draining lymphatics and develop models for regional lymphablation with surgery or radiation. We find that lymphablation eliminates the tumor ICI response, worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observe an upregulation of conventional type I dendritic cells and type I interferon signaling and show that both are necessary for the ICI response and lost with lymphablation. Ultimately, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational, lymphatic-preserving treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, control regional metastatic disease, and confer durable antitumor immunity., (© 2022. The Author(s).)