Targeting Ubiquitin-like Protein, ISG15, as a Novel Tumor Associated Antigen in Colorectal Cancer.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in both men and women in the United States. While immune checkpoint inhibitor (ICI) therapy is demonstrating remarkable clinical responses, the resistance and immune-related toxicities associated with ICIs demonstrate the need to develop additional immunotherapy options for CRC patients. Cancer vaccines represent a safe and promising treatment approach for CRC. As previously developed tumor-associated antigen (TAA)-based cancer vaccines for CRC are not demonstrating promising results, we propose that interferon-stimulated gene 15 (ISG15) is a novel TAA and therapeutic target for CRC. Our work demonstrates the anti-tumor efficacy of a Listeria-based vaccine targeting ISG15, designated Lm-LLO-ISG15, in an immunocompetent CRC murine model. The Lm-LLO-ISG15-mediated anti-tumor response is associated with an increased influx of functional T cells, higher production of multiple intracellular cytokines response, a lower number of regulatory T cells, and a greater ratio of effector to regulatory T cells (Teff/Treg) in the tumor microenvironment.

Dynamic tumor microenvironment, molecular heterogeneity, and distinct immunologic portrait of triple-negative breast cancer: an impact on classification and treatment approaches.

Heterogeneity of the tumor microenvironment (TME) and the lack of a definite targetable receptor in triple-negative breast cancer (TNBC) has carved a niche for this cancer as a particularly therapeutically challenging form of breast cancer. However, recent advances in high-throughput genomic analysis have provided new insights into the unique microenvironment and defining characteristics of various subsets of TNBC. This improved understanding has contributed to the development of novel therapeutic strategies including targeted therapies such as PARP inhibitors and CDK inhibitors. Moreover, the recent FDA approval of the immune checkpoint inhibitor against programmed cell death protein 1 (PD-1), pembrolizumab and atezolizumab, holds the promise of improving the quality of life and increasing the overall survival of TNBC patients. This recent approval is one of the many therapeutically novel strategies that are currently being exploited in clinical trials toward eventual contribution to the oncologist's toolbox against TNBC. In this review, we comprehensively discuss TNBC's distinct TME and its immunophenotype. Furthermore, we highlight the histological and molecular classification of this cancer. More importantly, we describe how these characteristics and classifications contribute to the current standards of care and how they steer the development of newer and more targeted therapies toward achieving peak therapeutic goals in the treatment of TNBC.

A Listeria-based vaccine targeting ISG15 exerts anti-tumor efficacy in renal cell carcinoma.

Renal cell carcinoma (RCC) is the deadliest form of urological cancer and is projected to be the fourth most common neoplasm in the USA in males by 2040. In addition to the current poor prognosis with 5-year survival rates hardly reaching 15%, the prevalence of resistance to currently available systemic therapies has also established an urgent need to develop new treatment regimen(s) for advanced RCC. Interferon-stimulated gene 15 (ISG15) is the first identified ubiquitin-like modifier and has been intensively studied for its central role in innate immunity against intracellular pathogens. However, in this study, we identified ISG15 as a novel tumor-associated antigen and prognostic marker in RCC. Further, we therapeutically targeted elevated ISG15 expression by means of a Listeria monocytogenes (Lm)-based vaccine, designated Lm-LLO-ISG15, in both subcutaneous and orthotopic RCC mouse models. Treatment with Lm-LLO-ISG15 resulted in an influx of tumor-infiltrating effector T cells and significant anti-tumor efficacy in both subcutaneous and orthotopic RCC tumor models. Treatment with Lm-LLO-ISG15 also generated a robust interferon-gamma response and attracted a larger pool of polyfunctional T cells into the tumor microenvironment. Importantly, the therapeutic efficacy of Lm-LLO-ISG15 in RCC is comparable to that of anti-PD-1 and sunitinib, the current frontline therapies for RCC patients. Collectively, our work illustrates that targeting ISG15 in RCC with a CTL-based immunotherapy such as Lm-LLO-ISG15 is a promising and potentially translatable therapeutic strategy to enhance survival in RCC patients.

Synergistic potential of immune checkpoint inhibitors and therapeutic cancer vaccines.

Cancer vaccines and immune checkpoint inhibitors (ICIs) function at different stages of the cancer immune cycle due to their distinct mechanisms of action. Therapeutic cancer vaccines enhance the activation and infiltration of cytotoxic immune cells into the tumor microenvironment (TME), while ICIs, prevent and/or reverse the dysfunction of these immune cells. The efficacy of both classes of immunotherapy has been evaluated in monotherapy, but they have been met with several challenges. Although therapeutic cancer vaccines can activate anti-tumor immune responses, these responses are susceptible to attenuation by immunoregulatory molecules. Similarly, ICIs are ineffective in the absence of tumor-infiltrating lymphocytes (TILs). Further, ICIs are often associated with immune-related adverse effects that may limit quality of life and compliance. However, the combination of the improved immunogenicity afforded by cancer vaccines and restrained immunosuppression provided by immune checkpoint inhibitors may provide a suitable platform for therapeutic synergism. In this review, we revisit the history and various classifications of therapeutic cancer vaccines. We also provide a summary of the currently approved ICIs. Finally, we provide mechanistic insights into the synergism between ICIs and cancer vaccines.

Listeria-based immunotherapy directed against CD105 exerts anti-angiogenic and anti-tumor efficacy in renal cell carcinoma.

Targeting tumor-associated angiogenesis is currently at the forefront of renal cell carcinoma (RCC) therapy, with sunitinib and bevacizumab leading to increased survival in patients with metastatic RCC (mRCC). However, resistance often occurs shortly after initiation of therapy, suggesting that targeting the tumor-associated vascular endothelium may not be sufficient to eradicate RCC. This study reports the therapeutic efficacy of a Listeria (Lm)-based vaccine encoding an antigenic fragment of CD105 (Lm-LLO-CD105A) that targets both RCC tumor cells and the tumor-associated vasculature. Lm-LLO-CD105A treatment reduced primary tumor growth in both subcutaneous and orthotopic models of murine RCC. The vaccine conferred anti-tumor immunity and remodeled the tumor microenvironment (TME), resulting in increased infiltration of polyfunctional CD8+ and CD4+ T cells and reduced infiltration of immunosuppressive cell types within the TME. We further provide evidence that the therapeutic efficacy of Lm-LLO-CD105A is mediated by CD8+ T cells and is dependent on the robust antigenic expression of CD105 by RCC tumor cells. The result from this study demonstrates the safety and promising therapeutic efficacy of targeting RCC-associated CD105 expression with Lm-based immunotherapy.