Immunotherapy for Gastrointestinal Cancer

Background: Colon adenocarcinoma (COAD) is the most common subtype of colon cancer, and cuproptosis is a recently newly defined form of cell death that plays an important role in the development of several malignant cancers. However, studies of cuproptosis-related lncRNAs (CRLs) involved in regulating colon adenocarcinoma are limited. The purpose of this study is to develop a new prognostic CRLs signature of colon adenocarcinoma and explore its underlying biological mechanism. Methods: In this study, we downloaded RNA-seq profiles, clinical data and tumor mutational burden (TMB) data from the TCGA database, identified cuproptosis-associated lncRNAs using univariate Cox, lasso regression analysis and multivariate Cox analysis, and constructed a prognostic model with risk score based on these lncRNAs. COAD patients were divided into high- and low-risk subgroups based on the risk score. Cox regression was also used to test whether they were independent prognostic factors. The accuracy of this prognostic model was further validated by receiver operating characteristic curve (ROC), C-index and Nomogram. In addition, the lncRNA/miRNA/mRNA competing endogenous RNA (ceRNA) network and protein–protein interaction (PPI) network were constructed based on the weighted gene co-expression network analysis (WGCNA). Results: We constructed a prognostic model based on 15 cuproptosis-associated lncRNAs. The validation results showed that the risk score of the model (HR = 1.003, 95% CI = 1.001–1.004; p < 0.001) could serve as an independent prognostic factor with accurate and credible predictive power. The risk score had the highest AUC (0.793) among various factors such as risk score, stage, gender and age, also indicating that the model we constructed to predict patient survival was better than other clinical characteristics. Meanwhile, the possible biological mechanisms of colon adenocarcinoma were explored based on the lncRNA/miRNA/mRNA ceRNA network and PPI network constructed by WGCNA. Conclusion: The prognostic model based on 15 cuproptosis-related lncRNAs has accurate and reliable predictive power to effectively predict clinical outcomes in colon adenocarcinoma patients. Full article

Background: Gastric cancer is a prevalent cause of tumor death. Tumor immunotherapy aims to reshape the specific immunity to tumors in order to kill the tumor. LncRNAs play a pivotal role in regulating the tumor immune microenvironment. Herein, immune-related lncRNAs were used to establish a prognosis risk-assessment model for gastric cancer and provide personalized predictions while providing insights and targets for gastric cancer treatment to enhance patient prognosis. Methods: Gastric adenocarcinoma transcriptome and clinical data were acquired from the The Cancer Genome Atlas (TCGA) database to screen the immune-related lncRNAs. Then, LASSO COX regression was utilized to construct the prognosis risk-assessment model. Afterward, the reliability of the model was evaluated the relationship between immune infiltration, clinical characteristics, and the model was analyzed. Results: We identified 13 lncRNAs and constructed the prognosis assessment model. According to the median risk score of the training set, the patients were assigned to different risk groups. Overall survival time was shorter in the high-risk group. In the high-risk group, higher infiltration of mono-macrophages, dendritic cells, CD4+ T cells, and CD8+ T cells was observed. Moreover, the model was positively related to tumor metastasis. Conclusion: The prognosis risk-assessment model developed in this research can effectively predict the prognosis of gastric cancer patients. This tool is expected to be further applied to clinics in the future, thus providing a novel target for immunotherapy in gastric cancer patients. Full article

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths in the world. More than half of patients with HCC present with advanced stage, and highly active systemic therapies are crucial for improving outcomes. Immune checkpoint inhibitor (ICI)-based therapies have emerged as novel therapy options for advanced HCC. Only one third of patients achieve an objective response with ICI-based therapies due to primary resistance or acquired resistance. The liver tumor microenvironment is naturally immunosuppressive, and specific mutations in cell signaling pathways allow the tumor to evade the immune response. Next, gene sequencing of the tumor tissue or circulating tumor DNA may delineate resistance mechanisms to ICI-based therapy and provide a rationale for novel combination therapies. In this review, we discuss the results of key clinical trials that have led to approval of ICI-based therapy options in advanced HCC and summarize the ongoing clinical trials. We review resistance mechanisms to ICIs and discuss how immunotherapies may be optimized based on the emerging research of tumor biomarkers and genomic alterations. Full article

Gastroentero-pancreatic Neuroendocrine Neoplasms (GEP-NENs) are a diverse group of rare tumors that arise from neuroendocrine cells in the gastrointestinal tract and pancreas, and they can vary significantly in terms of clinical behavior and prognosis. Immunotherapy, particularly immune checkpoint inhibitors, has shown remarkable success in various malignancies by harnessing the body’s immune system to target and eliminate cancer cells. Immune checkpoint inhibitor clinical studies in GEP-NENs have yielded promising outcomes, particularly in individuals with advanced and refractory disease. Objective responses and disease stabilization have been observed in some cases, even in those previously unresponsive to traditional treatments like chemotherapy or targeted therapies. However, it’s important to note that the efficacy of immunotherapy in GEP-NENs can vary widely depending on tumor characteristics, the immune microenvironment, and patient factors. As such, identifying predictive biomarkers to select the most suitable patients for immunotherapy remains an ongoing challenge. Immunotherapy has considerable potential for treating GEP-NENs, but research is still in its early stages. Several combinations are being explored to enhance the effectiveness of immunotherapy and improve the outcomes of treatment, such as combining immunotherapy with other targeted therapies or chemotherapy. Full article

Oncological outcomes are improving in gastrointestinal cancer with advancements in systemic therapies, and there is notable potential in combining immunotherapy and radiation therapy (RT) to allow for further improvements. Various preclinical and early phase II studies have shown promising synergy with immunotherapy and RT in gastrointestinal cancer. A few recent phase III studies have shown improved survival with the addition of immunotherapy to standard treatment for gastrointestinal cancer. The timing, duration, sequencing, and integration with other anti-cancer treatments are still areas of ongoing research. We have reviewed the published and ongoing studies of the combinations of immunotherapy and RT in gastrointestinal cancers. Full article

The incidence and mortality of squamous cell carcinoma of the anus has been gradually increasing globally over the last few decades. The evolution of different modalities, including immunotherapies, has changed the treatment paradigm of metastatic anal cancers. Chemotherapy, radiation therapy, and immune-modulating therapies form the backbone of treatment of anal cancer in various stages. Most anal cancers are linked to high-risk human papilloma virus (HPV) infections. HPV oncoproteins E6 and E7 are responsible for an anti-tumor immune response triggering the recruitment of tumor-infiltrating lymphocytes. This has led to the development and utilization of immunotherapy in anal cancers. Current research in anal cancer is moving forward to discover ways to incorporate immunotherapy in the treatment sequencing in various stages of anal cancers. Immune checkpoint inhibitors alone or in combination, adoptive cell therapy, and vaccines are the areas of active investigations in anal cancer in both locally advanced and metastatic settings. Immunomodulating properties of non-immunotherapies are incorporated to enhance immune checkpoint inhibitors’ effectiveness in some of the clinical trials. The aim of this review is to summarize the potential role of immunotherapy in anal squamous cell cancers and future directions. Full article

Immunotherapy has remained at the vanguard of promising cancer therapeutic regimens due to its exceptionally high specificity for tumor cells and potential for significantly improved treatment-associated quality of life compared to other therapeutic approaches such as surgery and chemoradiation. This is especially true in the digestive system, where high rates of mutation give rise to a host of targetable tumor-specific antigens. Many patients, however, do not exhibit measurable improvements under immunotherapy due to intrinsic or acquired resistance, making predictive biomarkers necessary to determine which patients will benefit from this line of treatment. Many of these biomarkers are assessed empirically by pathologists according to nuanced scoring criteria and algorithms. This review serves to inform clinicians and pathologists of extant and promising upcoming biomarkers predictive of immunotherapeutic efficacy among digestive system malignancies and the ancillary testing required for interpretation by pathologists according to tumor site of origin. Full article

Pancreatic adenocarcinoma remains one of the most lethal cancers globally, with a significant need for improved therapeutic options. While the recent breakthroughs of immunotherapy through checkpoint inhibitors have dramatically changed treatment paradigms in other malignancies based on considerable survival benefits, this is not so for pancreatic cancer. Chemotherapies with modest benefits are still the cornerstone of advanced pancreatic cancer treatment. Pancreatic cancers are inherently immune-cold tumors and have been largely refractory to immunotherapies in clinical trials. Understanding and overcoming the current failures of immunotherapy through elucidating resistance mechanisms and developing novel therapeutic approaches are essential to harnessing the potential durable benefits of immune-modulating therapy in pancreatic cancer patients. Full article

Background: Rectal gastrointestinal stromal tumours (GISTs) have many treatment options, but uncertainty remains regarding the best treatment regimen for this rare pathology. The aim of this review is to assess the optimal management approach including timing of chemotherapy. Methods: PubMed, EMBASE, and Cochrane databases were searched for relevant articles comparing the impact of radical vs. local excision, and neoadjuvant vs. adjuvant therapy had on outcomes in the management of rectal GISTs. We specifically evaluated the influence that the aforementioned factors had on margins, recurrence, overall survival, 5-year disease-free survival, and hospital length of stay. Results: Twenty-eight studies met our predefined criteria and were included in our study, twelve of which were included in the quantitative synthesis. When comparing neoadjuvant versus adjuvant chemotherapy, our meta-analysis noted no significance in terms of margin negativity (R0) (odds ratio [OR] 2.01, 95% confidence interval [CI], 0.7–5.79, p = 0.20) or recurrence rates (OR 0.22, 95% CI, 0.02–1.91, p = 0.17). However, there was a difference in overall 5-year survival in favour of neoadjuvant therapy (OR 3.19, 95% CI, 1.37–7.40, * p = 0.007). Comparing local excision versus radical excision, our meta-analysis observed no significance in terms of overall 5-year survival (OR1.31, 95% CI, 0.81–2.12, p = 0.26), recurrence (OR 0.67, 95% CI, 0.40–1.13, p = 0.12), or 5-year disease-free survival (OR 1.10, 95% CI, 0.55–2.19, p = 0.80). There was a difference in length of hospital stay with a reduced mean length of stay in local excision group (mean difference [MD] 6.74 days less in the LE group; 95% CI, −6.92–−6.56, * p =< 0.00001) as well as a difference in R0 rates in favour of radical resection (OR 0.68, 95% CI, 0.47–0.99, * p = 0.05). Conclusion: Neoadjuvant chemotherapy is associated with improved overall 5-year survival, while local excision is associated with reduced mean length of hospital stay. Further large-volume, prospective studies are required to further define the optimal treatment regimen in this complex pathology. Full article