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Vaccines
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Vaccines Targeting the Tumor Microenvironment: Challenges and Future Prospects
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Vaccines Targeting the Tumor Microenvironment: Challenges and Future Prospects

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Cancer Vaccines and Immunotherapy".

Deadline for manuscript submissions: 31 August 2025 | Viewed by 9733

Special Issue Editors

Prof. Dr. Walter J. Storkus

E-Mail Website
Guest Editor
1. Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA
2. UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
Interests: angiogenesis; cancer immunology; cancer immunotherapy; cancer vaccines; CD8+ T cells; chemokines; dendritic cells; pericytes; tertiary lymphoid structures; tumor microenvironment; vascular endothelial cells
Dr. Devin Lowe

E-Mail Website
Guest Editor
Department Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
Interests: tumor angiogenesis; cancer immunology; cancer immunotherapy; cancer vaccines; antibodies

Special Issue Information

Dear Colleagues,

Immunotherapies integrating immune checkpoint inhibitors (ICI) represent the current standard of care in the setting of many forms of solid cancer, yet they effectively treat only a minority of patients and are leveraged by the prerequisite for the presence of tumor-reactive T (or B) cells in the patient at baseline. To augment levels of such therapeutic immune effector cells, active vaccination approaches are warranted as priming regimens prior to the administration of ICI or for inclusion in combination intervention protocols to improved patient outcomes. Although cancer vaccines have traditionally targeted tumor cell-associated antigens (including mutated neoantigens), the tumor microenvironment can enforce altered epigenetic programming in its component (non-tumor) stromal cell populations including cancer-associated fibroblasts (CAFs), vascular pericytes/mural cells, and vascular endothelial cells, among others, providing a diverse array of TME-associated antigens capable of being differentially recognized vs. normal tissues by the adaptive immune system. In this Special Issue, we welcome the submission of articles focused on cutting-edge vaccine-based approaches to improve the host response to cancer when applied as monotherapies or in combination with alternate immunotherapies such as ICI, TME conditioning agents, adoptive (T/CAR-T) cell therapies, or others.

Prof. Dr. Walter J. Storkus
Dr. Devin Lowe
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • vaccine
  • adoptive cell therapy
  • CAR-T cells
  • immune checkpoint inhibitors
  • immunotherapy
  • stroma
  • tumor microenvironment

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Published Papers (7 papers)

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Research

Jump to: Review, Other

11 pages, 2051 KiB  
Article
Identification and Validation of Th1-Selective Epitopes Derived from Proteins Overexpressed in Breast Cancer Stem Cells
by Denise L. Cecil, Daniel Herendeen, Meredith Slota, Megan M. O’Meara, Yushe Dang, Lauren Corulli and Mary L. Disis
Vaccines 2025, 13(5), 525; https://doi.org/10.3390/vaccines13050525 - 15 May 2025
Abstract
Background: Breast cancer stem cells (CSCs), particularly those enriched in triple-negative breast cancer (TNBC), are key contributors to tumor recurrence, metastasis, and resistance to therapy. CSCs often undergo epithelial-to-mesenchymal transformation (EMT), enhancing their invasiveness. Immune-based strategies that selectively target CSC/EMT antigens offer a [...] Read more.
Background: Breast cancer stem cells (CSCs), particularly those enriched in triple-negative breast cancer (TNBC), are key contributors to tumor recurrence, metastasis, and resistance to therapy. CSCs often undergo epithelial-to-mesenchymal transformation (EMT), enhancing their invasiveness. Immune-based strategies that selectively target CSC/EMT antigens offer a promising therapeutic approach. Methods: Twelve candidate CSC/EMT-associated proteins were identified through a systematic literature review. Human serum samples were assessed for antigen-specific IgG using ELISA. Th1/Th2 cytokine profiles, in response to predicted MHC II epitopes, were measured by ELISPOT in PBMCs. Epitope immunogenicity and tumor inhibition were evaluated in murine models, using either TNBC or luminal B syngeneic breast cancer cell lines. Results: Six of the candidate proteins (SOX2, YB1, FOXQ1, MDM2, CDH3, CD105) elicited antigen-specific IgG in human serum. Th1-selective epitopes, defined by high Th1/Th2 ratios, were identified for five of these proteins. Immunization of mice with peptide pools derived from CD105, CDH3, MDM2, SOX2, and YB1 induced significant antigen-specific IFN-γ responses. Tumor growth was significantly inhibited in the vaccinated mice across both the TNBC and luminal B breast cancer models, with mean tumor volume reductions ranging from 61% to 70%. Conclusions: CSC/EMT-associated antigens are immunogenic in humans and can be targeted using Th1-selective epitope-based vaccines. Immunization with these epitopes effectively inhibits tumor growth in multiple murine models of breast cancer. These findings support further clinical evaluation of CSC/EMT-targeted vaccines, especially for high-risk or advanced-stage breast cancer patients. Full article
(This article belongs to the Special Issue Vaccines Targeting the Tumor Microenvironment: Challenges and Future Prospects)
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10 pages, 992 KiB  
Article
A Phase II Study of Denileukin Diftitox in Patients with Advanced Treatment Refractory Breast Cancer
by William R. Gwin III, Lupe G. Salazar, James Y. Dai, Doreen Higgins, Andrew L. Coveler, Jennifer S. Childs, Rosie Blancas, Yushe Dang, Jessica Reichow, Meredith Slota, Hailing Lu and Mary L. Disis
Vaccines 2025, 13(2), 117; https://doi.org/10.3390/vaccines13020117 - 24 Jan 2025
Viewed by 840
Abstract
Background/Objectives: Regulatory T cells (Treg) suppress immunity in the tumor microenvironment, are linked to poor prognosis across breast cancer subtypes, and suppress the cytolytic function of cytotoxic CD8+ T cells. Denileukin diftitox, a diphtheria toxin (DT)/IL-2 fusion protein, targets and depletes Tregs. [...] Read more.
Background/Objectives: Regulatory T cells (Treg) suppress immunity in the tumor microenvironment, are linked to poor prognosis across breast cancer subtypes, and suppress the cytolytic function of cytotoxic CD8+ T cells. Denileukin diftitox, a diphtheria toxin (DT)/IL-2 fusion protein, targets and depletes Tregs. This Phase II study aimed to assess the safety of denileukin diftitox and its effect on Tregs and tumor growth in patients with advanced breast cancer. Methods: This single-arm Phase II study of denileukin diftitox enrolled patients with refractory stage IV breast cancer. Patients received denileukin diftitox 18 mcg/kg/day IV for Days 1–5 every 21 days for up to six cycles. Toxicity was assessed using CTCAE v3.0 and tumor response was evaluated per RECIST criteria. Blood samples were collected to analyze Tregs by flow cytometry and anti-DT antibodies by ELISA. Results: Fifteen patients with stage IV breast cancer were enrolled. Four patients completed all planned denileukin diftitox infusions and achieved stable disease (27%, 95% CI [0.08, 0.55]). Two patients (13%) discontinued due to toxicity, and nine patients (60%) discontinued due to progressive disease. Eleven patients experienced at least one grade 3 or 4 adverse event. Although there was a general reduction in peripheral blood Tregs, the difference in CD4+CD25+FOXP3+ Tregs levels post-treatment was not statistically significant (p = 0.10). Six patients (40%) achieved ≥25% reductions in Tregs. A significant increase in anti-DT IgG antibodies was observed post-treatment (p < 0.005). Conclusions: Denileukin diftitox demonstrated moderate toxicity in this advanced breast cancer cohort. Denileukin diftitox modulated regulatory T cells. However, the majority of patients experienced disease progression in the study. Full article
(This article belongs to the Special Issue Vaccines Targeting the Tumor Microenvironment: Challenges and Future Prospects)
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14 pages, 2709 KiB  
Article
Therapeutic Anti-Tumor Efficacy of DC-Based Vaccines Targeting TME-Associated Antigens Is Improved When Combined with a Chemokine-Modulating Regimen and/or Anti-PD-L1
by Jennifer L. Taylor, Kathleen M. Kokolus, Per H. Basse, Jessica N. Filderman, Chloe E. Cosgrove, Simon C. Watkins, Andrea Gambotto, Devin B. Lowe, Robert P. Edwards, Pawel Kalinski and Walter J. Storkus
Vaccines 2024, 12(7), 777; https://doi.org/10.3390/vaccines12070777 - 15 Jul 2024
Viewed by 3119
Abstract
We previously reported that dendritic cell (DC)-based vaccines targeting antigens expressed by tumor-associated vascular endothelial cells (VECs) and pericytes effectively control tumor growth in translational mouse tumor models. In the current report, we examined whether the therapeutic benefits of such tumor blood vessel [...] Read more.
We previously reported that dendritic cell (DC)-based vaccines targeting antigens expressed by tumor-associated vascular endothelial cells (VECs) and pericytes effectively control tumor growth in translational mouse tumor models. In the current report, we examined whether the therapeutic benefits of such tumor blood vessel antigen (TBVA)-targeted vaccines could be improved by the cotargeting of tumor antigens in the s.c. B16 melanoma model. We also evaluated whether combination vaccines incorporating anti-PD-L1 checkpoint blockade and/or a chemokine-modulating (CKM; IFNα + TLR3-L [rintatolimod] + Celecoxib) regimen would improve T cell infiltration/functionality in tumors yielding enhanced treatment benefits. We report that DC–peptide or DC–tumor lysate vaccines coordinately targeting melanoma antigens and TBVAs were effective in slowing B16 growth in vivo and extending survival, with superior outcomes observed for DC–peptide-based vaccines. Peptide-based vaccines that selectively target either melanoma antigens or TBVAs elicited a CD8+ T cell repertoire recognizing both tumor cells and tumor-associated VECs and pericytes in vitro, consistent with a treatment-induced epitope spreading mechanism. Notably, combination vaccines including anti-PD-L1 + CKM yielded superior therapeutic effects on tumor growth and animal survival, in association with the potentiation of polyfunctional CD8+ T cell reactivity against both tumor cells and tumor-associated vascular cells and a pro-inflammatory TME. Full article
(This article belongs to the Special Issue Vaccines Targeting the Tumor Microenvironment: Challenges and Future Prospects)
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15 pages, 3867 KiB  
Article
STAT1-Deficient HPV E6/E7-Associated Cancers Maintain Host Immunocompetency against Therapeutic Intervention
by Ling Lim, Ming-Hung Hu, Darrell Fan, Hsin-Fang Tu, Ya-Chea Tsai, Michelle Cheng, Suyang Wang, Chih-Long Chang, Tzyy-Choou Wu and Chien-Fu Hung
Vaccines 2024, 12(4), 430; https://doi.org/10.3390/vaccines12040430 - 17 Apr 2024
Cited by 1 | Viewed by 2151
Abstract
Human papillomavirus (HPV) remains a global health concern because it contributes to the initiation of various HPV-associated cancers such as anal, cervical, oropharyngeal, penile, vaginal, and vulvar cancer. In HPV-associated cancers, oncogenesis begins with an HPV infection, which is linked to the activation [...] Read more.
Human papillomavirus (HPV) remains a global health concern because it contributes to the initiation of various HPV-associated cancers such as anal, cervical, oropharyngeal, penile, vaginal, and vulvar cancer. In HPV-associated cancers, oncogenesis begins with an HPV infection, which is linked to the activation of the Janus protein tyrosine kinase (JAK)/STAT signaling pathway. Various STAT signaling pathways, such as STAT3 activation, have been well documented for their tumorigenic role, yet the role of STAT1 in tumor formation remains unclear. In the current study, STAT1−/− mice were used to investigate the role of STAT1 in the tumorigenesis of a spontaneous HPV E6/E7-expressing oral tumor model. Subsequently, our candidate HPV DNA vaccine CRT/E7 was administered to determine whether the STAT1−/− host preserves a therapeutic-responsive tumor microenvironment. The results indicated that STAT1−/− induces robust tumorigenesis, yet a controlled tumor response was attained upon CRT/E7 vaccination. Characterizing this treatment effect, immunological analysis found a higher percentage of circulating CD4+ and CD8+ T cells and tumor-specific cytotoxic T cells. In addition, a reduction in exhaustive lymphocyte activity was observed. Further analysis of a whole-cell tumor challenge affirmed these findings, as spontaneous tumor growth was more rapid in STAT1−/− mice. In conclusion, STAT1 deletion accelerates tumorigenesis, but STAT1−/− mice maintains immunocompetency in CRT/E7 treatments. Full article
(This article belongs to the Special Issue Vaccines Targeting the Tumor Microenvironment: Challenges and Future Prospects)
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Review

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12 pages, 765 KiB  
Review
The Past, Present, and Future of Cervical Cancer Vaccines
by Alexander C. Lien, Grace S. Johnson, Tianyun Guan, Caitlin P. Burns, Jacob M. Parker, Lijun Dong, Mark R. Wakefield and Yujiang Fang
Vaccines 2025, 13(2), 201; https://doi.org/10.3390/vaccines13020201 - 17 Feb 2025
Viewed by 1003
Abstract
Since the introduction of prophylactic HPV vaccines, both HPV infection rates and cervical cancer rates have subsequently dropped. Yet, cervical cancer remains the fourth most common cancer diagnosis in women globally. As HPV and its role in the development of cervical cancer become [...] Read more.
Since the introduction of prophylactic HPV vaccines, both HPV infection rates and cervical cancer rates have subsequently dropped. Yet, cervical cancer remains the fourth most common cancer diagnosis in women globally. As HPV and its role in the development of cervical cancer become better understood, vaccines have emerged as a front runner for improved therapeutic cervical cancer treatment. Recent studies have shown that protein and DNA vaccines may be effectively delivered via the use of several different vectors, while combination therapy with immune checkpoint inhibitors provides even more effective treatment. Further investigation and additional clinical studies into specific vaccine strategies are necessary to determine how effective vaccines are as therapeutic treatment for cervical cancer. This review intends to summarize some of the most promising research on cervical cancer vaccines. Such a study may be helpful for gynecologists to prevent and manage patients with HPV infection. Full article
(This article belongs to the Special Issue Vaccines Targeting the Tumor Microenvironment: Challenges and Future Prospects)
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15 pages, 620 KiB  
Review
Lessons from Post-Immunotherapy Tumor Tissues in Clinical Trials: How Can We Fuel the Tumor Microenvironment in Gliomas?
by Lan Hoc Phung, Takahide Nejo and Hideho Okada
Vaccines 2024, 12(8), 862; https://doi.org/10.3390/vaccines12080862 - 1 Aug 2024
Viewed by 1412
Abstract
Despite recent advancements in cancer immunotherapy, many patients with gliomas and glioblastomas have yet to experience substantial therapeutic benefits. Modulating the tumor microenvironment (TME) of gliomas, which is typically “cold”, is crucial for improving treatment outcomes. Clinical tumor specimens obtained post-immunotherapy provide invaluable [...] Read more.
Despite recent advancements in cancer immunotherapy, many patients with gliomas and glioblastomas have yet to experience substantial therapeutic benefits. Modulating the tumor microenvironment (TME) of gliomas, which is typically “cold”, is crucial for improving treatment outcomes. Clinical tumor specimens obtained post-immunotherapy provide invaluable insights. However, access to such post-immunotherapy samples remains limited, even in clinical trials, as tumor tissues are often collected only at tumor relapse. Recent studies of neoadjuvant immunotherapy provided important insights by incorporating surgical resections of post-treatment tumors. Moreover, pre-surgical immunotherapies are increasingly integrated into clinical trial designs to evaluate treatment efficacy. These investigations reveal critical information, particularly regarding the delivery success of therapeutic agents, the expansion and persistence of immune products, and the cellular and molecular changes induced in the TME. In this review, we assess the findings on post-treatment tumor specimens obtained from recent immunotherapy clinical trials on gliomas, highlight the importance of these samples for understanding therapeutic impacts, and discuss proactive investigation approaches for future clinical trials. Full article
(This article belongs to the Special Issue Vaccines Targeting the Tumor Microenvironment: Challenges and Future Prospects)
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Other

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6 pages, 159 KiB  
Opinion
Unlocking mRNA Vaccine Potential in Liver Cancer Treatment via Synergistic Bile Acid Modulation
by Yuqian Wang, Rui Han and Changquan Ling
Vaccines 2025, 13(5), 502; https://doi.org/10.3390/vaccines13050502 - 9 May 2025
Viewed by 290
Abstract
This Letter to the Editor explores synergistic mechanisms enhancing mRNA cancer vaccine efficacy through bile acid metabolism modulation in liver cancer treatment. The latest evidence indicates that bile acids significantly impair T cell function within the liver cancer microenvironment, creating an immunosuppressive milieu [...] Read more.
This Letter to the Editor explores synergistic mechanisms enhancing mRNA cancer vaccine efficacy through bile acid metabolism modulation in liver cancer treatment. The latest evidence indicates that bile acids significantly impair T cell function within the liver cancer microenvironment, creating an immunosuppressive milieu that hampers anti-tumor responses. Modulating bile acid composition, particularly increasing ursodeoxycholic acid (UDCA), could reshape the tumor microenvironment (TME) to favor mRNA vaccine-induced T cell activity—a promising strategy to overcome current immunotherapy limitations in liver cancer. Full article
(This article belongs to the Special Issue Vaccines Targeting the Tumor Microenvironment: Challenges and Future Prospects)
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