Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
Gut microbial signature for combination immune checkpoint blockade across cancer types
May 2024—Immunotherapy has revolutionized cancer treatment by recruiting the patient’s immune system to detect and destroy cancer cells. Immunotherapy often involves immune checkpoint blockade (ICB) agents, which target negative regulators of T-cell activation, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1). Although ICB is used to treat a variety of cancer types, patients’ response to therapy is often unpredictable, and biomarkers such as tumor mutation burden, mismatch repair deficiency, and IHC for PD-L1 have limitations for assessing ICB response. Consequently, there is great interest in discovering additional biomarkers that will improve the ability to predict clinical response to ICB. Recent studies have explored the hypothesis that there may be a correlation between a person’s gut microbiome and therapeutic response. However, many of these studies have classified organisms only to the species level, with limited reproducibility. The authors of this study examined the hypothesis that deep shotgun metagnomic sequencing to identify variation in intraspecies strains may provide the resolution necessary to understand the relationship between gut microbiota and response to ICB regimens. They analyzed fecal samples from 106 patients enrolled in an Australian multi-center clinical trial focused on treating rare cancers, including upper intestinal and biliary cancers, neuroendocrine neoplasms, and gynecological tumors. The patients were treated with combination ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). Deep shotgun metagenomic sequencing of the fecal samples was performed to quantitatively assess the composition of the bacterial strains. A supervised machine learning framework was used to analyze how patients’ gut microbiota and other clinical features affected response to treatment with the combination ICB regimen. The authors confirmed that the model was most accurate when using strain-level microbial abundances compared with less specific microbial characterization, making the model relatively robust across the various cancer types. Examination of the features of the model that most contributed to predicting response identified 22 bacterial strains that were associated with response to combination ICB therapy in particular. Some of the strains associated with a greater beneficial response were within the Faecalibacterium genus, which has been previously described in a study that assessed anti-PD-1 monotherapy response in patients with melanoma and hepatobiliary cancers. To evaluate the generalizability of the microbial signature, the authors assessed the model in validation cohorts from multiple studies with comparable shotgun metagenomic data. These studies included patients from five countries who had a variety of tumor types and were treated with a variety of ICB regimens. The authors found that the model was more likely to predict response in patients receiving combination ICB therapy than in those receiving monotherapy. This implies that the relationship between the gut microbiome and ICB response may depend on the specific therapy combination. This study shows that with the advancement of precision medicine, understanding the complexities of the microbiome may prove useful in selecting immunotherapy treatment regimens.
Gunjur A, Shao Y, Rozday T, et al. A gut microbial signature for combination immune checkpoint blockade across cancer types. Nat Med. doi:10.1038/s41591-024-02823-z
Correspondence: Dr. Ashray Gunjur at [email protected] or Dr. Trevor Lawley at [email protected]
Role of smoking and diabetes in telomere shortening in alcohol use disorder
Alcohol abuse is one of the most common forms of substance abuse worldwide, with many adverse health and psychosocial consequences. It is also predicted to be a causal factor in a multitude of diseases, injuries, and other health conditions, although the health-related implications of alcohol are complicated by confounding factors, such as lifestyle habits. Several studies have examined the detrimental effects of alcohol abuse at the cellular level, focusing on accelerated cellular aging. Cellular aging can be characterized by analyzing telomeres, which are structures located at the ends of each chromosome that are composed of repetitive DNA sequences and specialized proteins. These structures are believed to protect the integrity of the chromosomes and are known to shorten each time a cell replicates, making them a potential indicator of aging. Factors such as socioeconomic status and psychological stress have been found to shorten telomeres. The authors of this study assessed factors that contribute to reduced telomere length in Japanese patients suffering from alcohol use disorder (AUD). The AUD group comprised 74 patients who were recently hospitalized with complications of AUD or had participated in treatment programs. A control group consisted of 68 relatively healthy people based on recent health checkups. Patients and control subjects answered a questionnaire survey that focused on drinking habits and characteristics, smoking history, and comorbidities. They also provided blood samples for real-time polymerase chain reaction assessment of leukocyte mean telomere length. After accounting for age, the authors determined that the AUD group had significantly shorter telomere lengths than the control group. Telomere length was noted to be shortened in the AUD cohort with chronic smoking status or a history of diabetes in particular. It previously has been shown that smoking and diabetes are independent factors that cause accelerated cellular aging. However the authors’ results suggest that there may be a compounding negative effect. This observation is pertinent considering that smoking is more prevalent in AUD patients than in the general population and that the incidence of diabetes increases with chronic heavy alcohol use. It was also observed that the effect of diabetes on telomere length may persist even in those with adequate diabetes management. However, this observation is based on a history of medical management rather than an assessment of blood glucose levels. This study was limited to patients in Japan and may benefit from a larger study population since there are known variations in telomere lengths and different propensities for comorbidities between ethnic groups. Increased awareness of the harmful effects of AUD and access to support groups and treatment programs may help limit AUD, and thereby reduce accelerated telomere shortening.
Inomata S, Arima H, Fukuda T, et al. Smoking and diabetes cause telomere shortening among alcohol use disorder patients. Sci Rep. 2024. doi:10.1038/s41598-024-55195-2
Correspondence: Dr. Hiroaki Arima at [email protected]