Due to increasing evidence that socioeconomic deprivation influences cancer outcomes through biological effects and care disparities, this single-institution retrospective study estimated associations between neighborhood-level socioeconomic deprivation, measured by the area deprivation index (ADI), and clinical outcomes among patients with metastatic solid tumors treated with immune checkpoint inhibitors (ICIs). Eligible patients included adults with metastatic solid tumors who received ICI between 2013 and 2024 and had a response assessment. Exclusions included adjuvant ICI receipt and missing ADI. Survival outcomes were estimated using the Kaplan-Meier method, and Cox regression models were used to measure associations between ADI and survival in the full cohort and stratified by tumor type. In a cohort of 691 patients with multiple solid tumor types and a median follow-up of 56.1 months, there was a trend toward shorter overall survival (OS) with increasing ADI quartile (HR=1.60 for the most vs. least deprived quartile), although not statistically significant ( P =0.143). There was no significant association between ADI and progression-free survival ( P =0.215). Exploratory analyses of tumor type subsets also revealed no statistically significant association between ADI and OS. In conclusion, there was no significant association between survival and ADI in this cohort. Further study in larger and more diverse cohorts is needed to elucidate the relationship between neighborhood-level socioeconomic deprivation and survival among patients with metastatic solid tumors receiving ICI.
Immune checkpoint inhibitors such as pembrolizumab can trigger immune-related adverse events, including rare sarcoidosis-like reactions (DISR), whose immunopathogenesis and clinical spectrum remain incompletely defined. We conducted a systematic review of all published cases of pembrolizumab-induced DISR, extracted and descriptively analyzed clinical, laboratory, imaging, and outcome data from 41 patients, and additionally report a 42-year-old woman who developed multiorgan DISR with a previously unreported metabolic complication involving dysregulated calcium homeostasis and ureteral double-J stent calcification. The median age at onset was 65 years, with melanoma as the most frequent underlying malignancy. Lymph nodes, lungs, and skin were the most commonly affected organs, and the median time to onset was 16 weeks, with some cases occurring after treatment discontinuation. ACE levels were elevated in 60% of cases, PET/CT showed increased FDG uptake in 95% of cases, and histologic confirmation was obtained in nearly all patients. Corticosteroids were the most frequent treatment, and 90.5% achieved stable disease or remission. Pembrolizumab-induced DISR is a rare irAE driven by immune dysregulation, and our case expands its clinical spectrum by identifying a novel manifestation of macrophage-mediated calcium dysregulation. Our pooled analysis of all published cases to date contributes to a broader understanding of this underrecognized entity. Early recognition is essential to avoid misdiagnosis of tumor progression, and DISR may serve as a potential biomarker of effective antitumor immune activation.
Oral squamous cell carcinoma (OSCC) is frequently refractory to immune checkpoint blockade, in part because the tumor microenvironment is enriched with immunosuppressive, M2-like tumor-associated macrophages. Auranofin (ARN), an FDA-approved thioredoxin reductase inhibitor, induces oxidative and proteotoxic stress and may remodel myeloid compartments to improve immunotherapy responsiveness. Here, we investigated whether ARN sensitizes OSCC to PD-1 blockade through DUSP1-associated macrophage reprogramming. Using an immunotherapy-resistant, syngeneic MOC2 murine OSCC model, mice bearing established tumors were treated with vehicle, ARN, anti–PD-1, or combination therapy. Combination treatment significantly improved survival and produced the most pronounced reduction in tumor burden compared with control and monotherapy groups. In vitro, ARN increased Dusp1 mRNA in bone marrow–derived macrophages polarized toward an M2 phenotype in a time- and dose-dependent manner. In vivo, RNAscope analysis demonstrated increased Dusp1 expression within tumors following ARN and/or anti–PD-1, with co-localization patterns consistent with a shift toward a pro-inflammatory macrophage state. Functionally, ARN directly promoted macrophage repolarization, increasing the M1/M2 ratio by flow cytometry and suppressing expression of the M2 marker arginase-1 (Arg1). In tumors, ARN and anti–PD-1 each increased the frequency of M1-like macrophages while reducing M2-like populations. Adaptive immune profiling further showed increased CD8⁺ T-cell infiltration across treatments, peaking in the combination group. Tumor cells also upregulated PD-L1, PD-L2, and CTLA-4, consistent with heightened immune stress. Collectively, these findings support repurposing ARN as an immunomodulatory adjuvant to overcome resistance to PD-1 blockade in OSCC by inducing DUSP1-linked macrophage remodeling and enhancing cytotoxic T-cell–associated antitumor immunity.
Current evidence demonstrates the efficacy of anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in patients with recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC), but only a limited number of patients can benefit. TP53 alteration is one of the most frequent genetic events in HNSCC and may be reflected by aberrant p53 protein expression in tumor cells. Nevertheless, the association between p53 immunohistochemical expression and clinical outcomes in RMHNSCC patients receiving anti-PD-1 therapy remains unclear. We retrospectively analyzed 141 patients with recurrent or metastatic HNSCC who received anti-PD-1 ICIs between January 2017 and December 2023. Immunohistochemical staining in the pretreatment tumor was used to evaluate the expression of p53 and was correlated with the treatment outcome of anti-PD-1 ICIs. Positive p53 expression and tumor proportion score (TPS) <50% were significantly correlated with a poor response to anti-PD-1 ICIs. The overall response rates were 31% and 11% in patients with negative and positive p53 expressions, respectively ( P =0.008). Univariate survival analysis showed that positive p53 expression ( P =0.012) and TPS <50% ( P =0.035) were significantly associated with worse progression-free survival (PFS), and positive p53 expression ( P <0.001) was significantly correlated with inferior overall survival (OS). Multivariate analysis revealed that positive p53 expression was an independent poor prognosticator for worse PFS and inferior OS. The 2-year PFS and OS rates were 16% and 32% in patients with negative p53 expression and 8% and 10% in patients with positive p53 expression, respectively. In conclusion, p53 expression in pretreatment tumor specimens was associated with response and survival outcomes in patients with RMHNSCC receiving anti-PD-1 ICIs. Positive p53 expression may serve as a potential prognostic marker for inferior clinical outcomes in this population. Further prospective studies incorporating TP53 sequencing and immune microenvironmental profiling are warranted to validate its clinical utility.
Neoadjuvant immunotherapy (NAIC) is feasible and associated with a high rate of pathologic complete response (pCR) in deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) gastric and gastroesophageal junction cancers (GC/GEJC). However, the association between NAIC efficacy and pathologic characteristics remains unclear. We conducted a retrospective study to evaluate this relationship. Patients with dMMR/MSI-H GC/GEJC who received neoadjuvant immunotherapy were included. The effects of different neoadjuvant regimens were compared, and pathologic characteristics were analyzed between tumor regression grade TRG1 and TRG2 groups. The χ 2 test was used to estimate relative risks (RRs) with 95% CIs. In total, 39 patients with dMMR/MSI-H GC/GEJC who received neoadjuvant immunotherapy were included. All patients underwent complete R0 resection; 22 patients (56%) achieved pCR in both the primary tumor and lymph nodes. The chemotherapy plus immunotherapy group and the immunotherapy-only group achieved significantly higher TRG1 rates compared with the chemotherapy group (RR=4.2, 95% CI=1.5–15.0, P =0.0004; and RR=4.4, 95% CI=1.7–15.7, P =0.003, respectively). The intestinal subtype also demonstrated a higher TRG1 rate than the mixed subtype (RR=2.5, 95% CI=1.1–8.7, P =0.0196). Neoadjuvant immunotherapy achieved a high pCR rate in patients with dMMR/MSI-H locally advanced, resectable GC/GEJC relative to chemotherapy. The intestinal subtype may serve as a histologic biomarker of enhanced sensitivity to neoadjuvant immunotherapy in this patient population.
