Systemic versus localized Bacillus Calmette Guérin immunotherapy of bladder cancer promotes an anti-tumoral microenvironment: Novel role of trained immunity.

Treatment for higher-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG); however, disease recurrence and progression occur frequently. Systemic immunity is critical for successful cancer immunotherapy; thus, recurrence of NMIBC may be due to suboptimal systemic activation of anti-tumor immunity after local immunotherapy. We previously reported that systemically acquired trained immunity (a form of innate immune memory) in circulating monocytes is associated with increased time-to-recurrence in patients with NMIBC treated with BCG. Herein, we used a mouse model of NMIBC to compare the effects of intravesical versus intravenous (systemic) BCG immunotherapy on the local and peripheral immune microenvironments. We also assessed whether BCG-induced trained immunity modulates anti-tumor immune responses. Compared with intravesical BCG, which led to a tumor-promoting immune microenvironment, intravenous BCG resulted in an anti-tumoral bladder microenvironment characterized by increased proportions of cytotoxic T lymphocytes (CTLs), and decreased proportions of myeloid-derived suppressor cells. Polarization toward anti-tumoral immunity occurred in draining lymph nodes, spleen, and bone marrow following intravenous versus intravesical BCG treatment. Pre-treatment with intravesical BCG was associated with increased rate of tumor growth compared with intravenous BCG pre-treatment. Trained immunity contributed to remodeling of the tumor immune microenvironment, as co-instillation of BCG-trained macrophages with ovalbumin-expressing bladder tumor cells increased the proportion of tumor-specific CTLs. Furthermore, BCG-trained dendritic cells exhibited enhanced antigen uptake and presentation and promoted CTL proliferation. Our data support the concept that systemic immune activation promotes anti-tumor responses, and that BCG-induced trained immunity is important in driving anti-tumor adaptive immunity.

Neoadjuvant Chemoimmunotherapy for NSCLC: A Systematic Review and Meta-Analysis.

Importance: To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%. Objective: To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials. Data Sources: MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of neoadjuvant chemoimmunotherapy and chemotherapy that included at least 10 patients. Study Selection: Observational studies and trials reporting the use of neoadjuvant radiotherapy, including chemoradiotherapy, molecular targeted therapy, or immunotherapy monotherapy, were excluded. Main Outcomes and Measures: Surgical, pathological, and efficacy end points and adverse events were pooled using a random-effects meta-analysis. Results: Among 43 eligible trials comprising 5431 patients (4020 males [74.0%]; median age range, 55-70 years), there were 8 randomized clinical trials with 3387 patients. For randomized clinical trials, pooled overall survival (hazard ratio, 0.65; 95% CI, 0.54-0.79; I2 = 0%), event-free survival (hazard ratio, 0.59; 95% CI, 0.52-0.67; I2 = 14.9%), major pathological response (risk ratio, 3.42; 95% CI, 2.83-4.15; I2 = 31.2%), and complete pathological response (risk ratio, 5.52; 95% CI, 4.25-7.15; I2 = 27.4%) favored neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy. For patients with baseline tumor PD-L1 levels less than 1%, there was a significant benefit in event-free survival for neoadjuvant chemoimmunotherapy compared with chemotherapy (hazard ratio, 0.74; 95% CI, 0.62-0.89; I2 = 0%). Conclusion and Relevance: This study found that neoadjuvant chemoimmunotherapy was superior to neoadjuvant chemotherapy across surgical, pathological, and efficacy outcomes. These findings suggest that patients with resectable NSCLC with tumor PD-L1 levels less than 1% may have an event-free survival benefit with neoadjuvant chemoimmunotherapy.

Association of Histone H3 Trimethylation in Circulating Monocytes with Lack of Early Recurrence in Patients with Bladder Cancer following BCG Induction Therapy.

BACKGROUND: The mode of action of Bacillus Calmette-Guérin (BCG) in the treatment of patients with non-muscle invasive bladder cancer (NMIBC) is incompletely understood, but recent studies support an association between BCG-induced trained immunity in circulating monocytes and disease-free survival. OBJECTIVE: We compared epigenetic profiles in monocytes from NMIBC patients with early disease recurrence with those from recurrence-free patients. METHODS: We conducted chromatin immunoprecipitation and DNA sequencing (ChIP-seq) on monocytes from seven patients treated with BCG (four with early recurrences and three recurrence-free after one year) to determine genome-wide distribution and abundance of histone 3 lysine 4 trimethylation (H3K4me3) prior to and after five weeks of induction therapy. RESULTS: Genome-wide H3K4me3 profiles before or after BCG induction distinguished patients with early recurrences from those remaining recurrence-free. Furthermore, H3K4me3 levels at genes involved in specific pathways were increased in the recurrence-free group. Independent quantification showed increased H3K4me3 levels in elements of the Wnt and AMPK signaling pathways in the recurrence-free group before BCG initiation, while elements of the MAPK showed increased levels after five weeks of induction in the same group. Validation of these genes on an independent cohort of four additional patients that remained recurrence-free after one year and three with early recurrences revealed consistent increases in H3K4me3 levels associated with MAPK pathway genes after five weeks of BCG treatment in the recurrence-free group. CONCLUSIONS: Recurrence-free survival following BCG immunotherapy for NMIBC is associated with the accumulation of H3K4me3 at specific gene loci, and could lead to identification of prognostic biomarkers.