Chengwei Peng

Lung squamous cell carcinoma (LUSC) is an aggressive subtype of non–small cell lung cancer (NSCLC) with limited targeted therapeutic options and incompletely defined immunoregulatory dependencies. In this study, we identified atypical chemokine receptor 3 (ACKR3) as a squamous-enriched regulator that restrains malignant progression in LUSC. Integrative analyses of human LUSC datasets, autochthonous genetically engineered mouse models (GEMM), and ex vivo organoid systems showed that ACKR3 loss accelerated tumor growth and remodeled the immune microenvironment, marked by reduced CD8+ T-cell infiltration and increased T-cell exhaustion. Mechanistically, ACKR3 limited the activation of the macrophage migration inhibitory factor (MIF)–CD74–PD-L1 axis, thereby constraining tumor-cell PD-L1 expression and preserving antitumor immune surveillance. In preclinical LUSC models, treatment with the ACKR3-directed PD-L1 degrader, cytokine receptor–targeting chimera (KineTAC), a bispecific molecule that coengages ACKR3 and PD-L1 to promote lysosomal degradation of PD-L1, enhanced antitumor efficacy, particularly in combination with chemotherapy. Together, these findings define ACKR3 as a squamous-associated immune checkpoint regulator and nominate ACKR3-directed PD-L1 degradation as a tumor-selective therapeutic strategy for LUSC. Significance: ACKR3 is a lineage-imprinted checkpoint restraining MIF–CD74–driven PD-L1 induction in lung squamous cell carcinoma that can be harnessed for PD-L1 degradation to induce tumor-restricted checkpoint dismantling.

The emergence of immunotherapy has dramatically altered the landscape of cancer treatment, leading to improved clinical outcomes for several malignancies. However, gastrointestinal immune-related adverse events are commonly encountered, and among patients with underlying autoimmune disorders, the risks and sequelae of such events may be more significant. Here, we present the case of a 76-year-old woman who developed isolated enteritis with diffuse ulceration shortly after the initiation of ipilimumab and nivolumab and ultimately passed away from refractory gastrointestinal bleeding. The clinical, endoscopic, and histologic findings were suggestive of a preexisting enteropathy that was rapidly accelerated by immune checkpoint inhibitor exposure.

Inhibition of thymidylate synthase (TS) is a common mechanism in the treatment of colorectal cancer (CRC). 5-Flurouracil is an indirect inhibitor of TS that is commonly used in CRC treatment regimens. Raltitrexed is a direct TS inhibitor that was hypothesized to have better efficacy and toxicity in CRC due to its specific inhibition. To test this, a phase II ECOG-ACRIN trial testing raltitrexed was conducted. This trial took place from December 1995 to December 1998. Advanced CRC patients were enrolled into 3 strata: 1. No prior treatment 2. One prior line of 5-FU based regimen without leucovorin 3. One prior line of 5-FU based regimen with leucovorin. Raltitrexed 3 mg/m² was given every 3 weeks. A two-stage design with pre-specified ORR was utilized. Primary endpoints were ORR, toxicity, and prognostic value of TS expression by immunohistochemistry. Secondary endpoints were mPFS and mOS. 101 patients were enrolled. ORR, mPFS, and mOS (months) by stratum were: 1. 5-FU Naïve: 3%, 2.1 (95% CI 1.4, 2.7), 14.5 (95% CI 8.0, 19.9) 2. 5-FU regimen/no leucovorin: 4.2%, 2.6 (95% CI 1.4, 3.5), 12.5 (95% CI 5.0, 17.0) and 3. 5-FU regimen/leucovorin: 3.3%, 1.7 (95% CI 1.4, 2.3), 7.3 (95% CI 4.9, 14.3). Based on low ORR, the trial did not advance to the second stage. One PR occurred in the high TS expression group, none in low TS group. In this phase II trial, raltitrexed did not show significant response rates in patients with advanced CRC. Due to limited ORR of raltitrexed, value of TS expression as a biomarker was inconclusive. No new safety signals for raltitrexed were demonstrated.

Opinion Statement: Pancreatic adenocarcinoma remains a leading cause of cancer-related mortality worldwide. Although surgery can be curable for a subset of patients, the five-year overall survival remains less than 15%. Despite extensive molecular characterization of pancreatic cancer, cytotoxic chemotherapy has served as the major component in therapeutic management. A major driver of pancreatic adenocarcinoma is mutations in KRAS, present in over 90% of cases. However, attempts to inhibit KRAS through upstream and downstream targets through the mitogen-activated protein kinase pathway have not been successful in the past. Despite this, multiple KRAS inhibitors have recently entered clinical trials and have shown promising results. These inhibitors have the potential to dramatically alter the landscape of treatment. In parallel, immunological approaches utilizing vaccines and bispecific antibodies are also in clinical development. Given these rapid new developments, the future of pancreatic cancer treatment will likely be determined by discovering the appropriate combinations of targeted and immune-based treatments.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice .