The Prospect of Harnessing the Microbiome to Improve Immunotherapeutic Response in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma cancer (PDAC) is projected to become the second leading cause of cancer-related death in the United States by 2030. Patients are often diagnosed with advanced disease, which explains the dismal 5-year median overall survival rate of ~12%. Immunotherapy has been successful in improving outcomes in the past decade for a variety of malignancies, including gastrointestinal cancers. However, PDAC is historically an immunologically "cold" tumor, one with an immunosuppressive environment and with restricted entry of immune cells that have limited the success of immunotherapy in these tumors. The microbiome, the intricate community of microorganisms present on and within humans, has been shown to contribute to many cancers, including PDAC. Recently, its role in tumor immunology and response to immunotherapy has generated much interest. Herein, the current state of the interaction of the microbiome and immunotherapy in PDAC is discussed with a focus on needed areas of study in order to harness the immune system to combat pancreatic cancer.

Host Interactions with Engineered T-cell Micropharmacies.

Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with a killing mechanism orthogonal to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Herein, we expanded the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with T-cell receptor (TCR)-engineered T cells. We demonstrate that SEAKER cells localized specifically to tumors, and activated bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells were efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.

Host-cell Interactions of Engineered T cell Micropharmacies.

Genetically engineered, cytotoxic, adoptive T cells localize to antigen positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with an orthogonal killing mechanism to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Here, we also expand the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with TCR-engineered T cells. We demonstrate that SEAKER cells localize specifically to tumors, and activate bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells are efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.

The Influence of the microbiome on the innate immune microenvironment of solid tumors.

Cancer remains a leading cause of death despite many advances in medical and surgical therapy. In recent decades, the investigation for novel therapeutic strategies with greater efficacy and reduced side effects has led to a deeper understanding of the relationship between the microbiome and the immune system in the context of cancer. The ability of the immune system to detect and kill cancer is now recognized to be greatly influenced by the microbial ecosystem of the host. While most of these studies, as well as currently used immunotherapeutics, focus on the adaptive immune system, this minimizes the impact of the innate immune system in cancer surveillance and its regulation by the host microbiome. In this review, known influences of the microbiome on the innate immune cells in the tumor microenvironment will be discussed in the context of individual innate immune cells. Current and needed areas of investigation will highlight the field and its potential impact in the clinical treatment of solid malignancies.

Association of Medical Appointment Cancellation Rates on Survival After Esophagectomy for Esophageal Cancer.

BACKGROUND: Cancelled healthcare appointments, especially in patients with complex cancers, such as esophageal cancer, risk delayed treatment and adverse outcomes. We hypothesized that patients with greater rates of healthcare appointment cancellations would have decreased survival after esophagectomy for esophageal cancer. METHODS: A retrospective analysis of patients from a single institution who underwent esophagectomy for esophageal cancer between 2004 and 2020 was performed. Appointment cancellations were queried 2 years pre-/post-esophagectomy and categorized as medical or ancillary. Continuous and categorical variables were compared by Mann-Whitney and chi-squared analyses, respectively. Survival associations post-esophagectomy were made by Kaplan-Meier analysis. RESULT: Seventy-six patients were identified. Total medical and ancillary appointments post-esophagectomy increased by 188% and 136%, respectively. Per patient, there was a median increase of 57.5 medical appointments in the post-esophagectomy period. Of medical appointments, 23.7% were cancelled pre-esophagectomy but 33.4% post-esophagectomy (p < 0.001). This trend held true for ancillary appointments. Patients with increased medical cancellation rates post-esophagectomy had shortened recurrence-free (p = 0.09) and overall survival (p < 0.01) versus patients with low cancellation rates. CONCLUSION: A significant increase in healthcare appointments is seen after esophagectomy. Patients with increased healthcare appointment cancellations have decreased post-esophagectomy survival which presents an opportunity to intervene in patients who historically have a high cancellation rate.

Low-dose CDK4/6 inhibitors induce presentation of pathway specific MHC ligands as potential targets for cancer immunotherapy.

Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) lead to cell-cycle arrest but also trigger T cell-mediated immunity, which might be mediated by changes in human leukocyte antigen (HLA) ligands. We investigated the effects of CDK4/6i, abemaciclib and palbociclib, on the immunopeptidome at nontoxic levels in breast cancer cell lines by biochemical identification of HLA ligands followed by network analyses. This treatment led to upregulation of HLA and revealed hundreds of induced HLA ligands in breast cancer cell lines. These new ligands were significantly enriched for peptides derived from proteins involved in the "G1/S phase transition of cell cycle" including HLA ligands from CDK4/6, Cyclin D1 and the 26S regulatory proteasomal subunit 4 (PSMC1). Interestingly, peptides from proteins targeted by abemaciclib and palbociclib, were predicted to be the most likely to induce a T cell response. In strong contrast, peptides induced by solely one of the drugs had a lower T cell recognition score compared to the DMSO control suggesting that the observed effect is class dependent. This general hypothesis was exemplified by a peptide from PSMC1 which was among the HLA ligands with highest prediction scores and which elicited a T cell response in healthy donors. Overall, these data demonstrate that CDK4/6i treatment gives rise to drug-induced HLA ligands from G1/S phase transition, that have the highest chance for being recognized by T cells, thus providing evidence that inhibition of a distinct cellular process leads to increased presentation of the involved proteins that may be targeted by immunotherapeutic agents.