Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Microenvironment".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 23041

Special Issue Editors


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Guest Editor
Greater Poland Cancer Centre, Poznan University of Medical Sciences, 61-867 Poznan, Poland
Interests: melanoma; melanoma vaccines; cancer stem cells; melanoma stem cells; cancer immunotherapy; cancer immunology; acute phase response; IL-6; soluble IL-6 receptor; immunotherapy clinical trials
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
1. Department of Medical Biotechnology, Poznan University of Medical Sciences, 61-866 Poznan, Poland
2. Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, 61-866 Poznan, Poland
Interests: melanoma; melanoma vaccines; cancer stem cells; melanoma stem cells; cancer immunotherapy; cancer immunology; acute-phase response; IL-6; soluble IL-6 receptor; immunotherapy clinical trials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The tumor microenvironment (TME) affects the tumor growth, cancer progression, invasion, metastasis formation and disease severity. TME is treated as a unique type of tissue environment. At all stages of development, tumor cells interact with infiltrating cells of the immune system, connective tissue and extracellular matrix. Cell-to-cell interactions are both direct through membrane-bound receptors or indirect through soluble mediators. Within the TME significant metabolic alterations occur, such as oxygen saturation, which leads to hypoxia. Soluble factors inhibit the antitumor activity of immune cells and also induce the production of proangiogenic factors that promote the generation of blood vessels that nourish the rapidly growing tumor. Thus, TME participates in suppressing immune response and promoting resistance to effective therapies. The better understanding of the TME biology has contributed to the development of cancer treatment modalities such as cell therapy, cancer vaccines and monoclonal antibodies-based approaches. However, therapies directed on a single target have not yet reached the desired effect. Accordingly, combination therapies are being studied to induce a more potent anti-tumor immune response. In this Special Issue of Cells, we attempt to collect and present the different types of TME-targeted cancer therapies and the limitations of their effectiveness.

Dr. Mariusz Kaczmarek
Prof. Dr. Andrzej Mackiewicz
Guest Editors

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Published Papers (6 papers)

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Research

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15 pages, 2955 KiB  
Article
Circulating Melanoma Cell Numbers Correlate with TIGIT-Positive Cytotoxic T Cell Counts in Advanced-Stage Melanoma Patients
by Paula Kamińska, Karolina Buszka, Łukasz Galus, Maurycy Jankowski, Michał Nowicki, Jacek Mackiewicz, Mariusz Kaczmarek and Joanna Budna-Tukan
Cells 2023, 12(6), 856; https://doi.org/10.3390/cells12060856 - 9 Mar 2023
Cited by 1 | Viewed by 1392
Abstract
Despite the rising public awareness of the risk factors and the possible prevention of melanoma development, it remains challenging in terms of diagnosis and treatment. To improve the clinical situation of patients, it would be especially beneficial to develop prognostic methods for the [...] Read more.
Despite the rising public awareness of the risk factors and the possible prevention of melanoma development, it remains challenging in terms of diagnosis and treatment. To improve the clinical situation of patients, it would be especially beneficial to develop prognostic methods for the effective and continuous assessment of the disease course. The solution could lie in the selection of effective biomarkers derived from the tumor microenvironment, increasing the effectiveness of melanoma prognoses and monitoring. Hence, in this study, we evaluated the number of circulating melanoma cells (CMCs) in representative blood samples of melanoma patients vs. healthy controls, as well as the proportion of particular cytotoxic T cells in the total lymphocyte and leukocyte population as a reflection of immune resistance. The results were correlated with the clinical parameters of the patients to examine the potential value of CMC quantification and lymphoid cell phenotyping in melanoma diagnostics, prognostics, and treatment outcome monitoring. The CMC numbers were significantly higher in melanoma patients than in healthy controls. However, an analysis of the correlations between the baseline CMC counts and the clinical parameters found no significant results. In turn, we found significant differences between the groups in the percentage of various profiles of CD8+ cytotoxic T lymphocytes characterized by TIGIT and TIM-3 differential expression. Importantly, the CMC number correlated with CD8+TIGIT+ and CD8+TIGIT+TIM-3- cytotoxic T cell counts in the melanoma patient group. Considering the above, the combination of CMCs and the immunological status of the patient, as defined by the prevalence of selected immune cell types, seems to be a promising approach in melanoma diagnostics and prognostics. Full article
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16 pages, 2193 KiB  
Article
Myeloid-Derived Suppressor Cells (MDSC) in Melanoma Patients Treated with Anti-PD-1 Immunotherapy
by Katarzyna Tomela, Bernadeta Pietrzak, Łukasz Galus, Jacek Mackiewicz, Marcin Schmidt, Andrzej Adam Mackiewicz and Mariusz Kaczmarek
Cells 2023, 12(5), 789; https://doi.org/10.3390/cells12050789 - 2 Mar 2023
Cited by 5 | Viewed by 2506
Abstract
Myeloid-derived suppressor cells (MDSC) are a subset of immature myeloid cells with suppressive activity well described in the context of cancer. They inhibit anti-tumour immunity, promote metastasis formation and can lead to immune therapy resistance. In a retrospective study, blood probes of 46 [...] Read more.
Myeloid-derived suppressor cells (MDSC) are a subset of immature myeloid cells with suppressive activity well described in the context of cancer. They inhibit anti-tumour immunity, promote metastasis formation and can lead to immune therapy resistance. In a retrospective study, blood probes of 46 advanced melanoma patients were analysed before the first administration of anti-PD-1 immunotherapy and in the third month of treatment for MDSC, immature monocytic (ImMC), monocytic MDSC (MoMDSC) and granulocytic MDSC (GrMDSC) by multi-channel flow cytometry. Cell frequencies were correlated with response to immunotherapy, progression-free survival (PFS) and lactate dehydrogenase (LDH) serum level. Responders to anti-PD-1 therapy had higher MoMDSC levels (4.1 ± 1.2%) compared to non-responders (3.0 ± 1.2%) (p = 0.0333) before the first administration of anti-PD-1. No significant changes in MDSCs frequencies were observed in the groups of patients before and in the third month of therapy. The cut-off values of MDSCs, MoMDSCs, GrMDSCs and ImMCs for favourable 2- and 3-year PFS were established. Elevated LDH level is a negative prognostic factor of response to the treatment and is related to an elevated ratio of GrMDSCs and ImMCs level compared to patients’ LDH level below the cut-off. Our data may provide a new perspective for more careful consideration of MDSCs, and specially MoMDSCs, as a tool for monitoring the immune status of melanoma patients. Changes in MDSC levels may have a potential prognostic value, however a correlation with other parameters must be established. Full article
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15 pages, 2486 KiB  
Article
A Coculture Model Mimicking the Tumor Microenvironment Unveils Mutual Interactions between Immune Cell Subtypes and the Human Seminoma Cell Line TCam-2
by Fabian A. Gayer, Alexander Fichtner, Tobias J. Legler and Holger M. Reichardt
Cells 2022, 11(5), 885; https://doi.org/10.3390/cells11050885 - 4 Mar 2022
Cited by 8 | Viewed by 3117
Abstract
Testicular germ cell cancer (TGCC) is the most common type of cancer in young men. Seminomas account for around half of them and are characterized by a pronounced infiltration of immune cells. So far, the impact of the tumor microenvironment (TME) on disease [...] Read more.
Testicular germ cell cancer (TGCC) is the most common type of cancer in young men. Seminomas account for around half of them and are characterized by a pronounced infiltration of immune cells. So far, the impact of the tumor microenvironment (TME) on disease progression, especially the interaction of individual immune cell subtypes with the tumor cells, remains unclear. To address this question, we used an in vitro TME model involving the seminoma-derived cell line Tcam-2 and immune cell subsets purified from human peripheral blood. T cells and monocytes were strongly activated when individually cocultured with Tcam-2 cells as revealed by increased expression of activation markers and pro-inflammatory cytokines both on the mRNA and protein level. Importantly, the interaction between tumor and immune cells was mutual. Gene expression of pluripotency markers as well as markers of proliferation and cell cycle activity were upregulated in Tcam-2 cells in cocultures with T cells, whereas gene expression of SOX17, a marker for seminomas, was unaltered. Interestingly, the impact of monocytes on gene expression of Tcam-2 cells was less pronounced, indicating that the effects of individual immune cell subsets on tumor cells in the TME are highly specific. Collectively, our data indicate that seminoma cells induce immune cell activation and thereby generate a strong pro-inflammatory milieu, whereas T cells conversely increase the proliferation, metastatic potential, and stemness of tumor cells. Although the employed model does not fully mimic the physiological situation found in TGCC in vivo, it provides new insights potentially explaining the connection between inflammatory infiltrates in seminomas and their tendency to burn out and metastasize. Full article
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Review

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27 pages, 411 KiB  
Review
Cancer Vaccine Therapeutics: Limitations and Effectiveness—A Literature Review
by Mariusz Kaczmarek, Justyna Poznańska, Filip Fechner, Natasza Michalska, Sara Paszkowska, Adrianna Napierała and Andrzej Mackiewicz
Cells 2023, 12(17), 2159; https://doi.org/10.3390/cells12172159 - 28 Aug 2023
Cited by 19 | Viewed by 4022
Abstract
In recent years, there has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and enhance the body’s natural immune response against cancer cells by utilizing specific antigens present in the tumor microenvironment. The goal [...] Read more.
In recent years, there has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and enhance the body’s natural immune response against cancer cells by utilizing specific antigens present in the tumor microenvironment. The goal is to achieve a complete clinical response, where all measurable cancer cells are either eliminated or greatly reduced in size. With their potential to revolutionize cancer treatment, these therapies represent a promising avenue for researchers and clinicians alike. Despite over 100 years of research, the success of therapeutic cancer vaccines has been variable, particularly in advanced cancer patients, with various limitations, including the heterogeneity of the tumor microenvironment, the presence of immunosuppressive cells, and the potential for tumor escape mechanisms. Additionally, the effectiveness of these therapies may be limited by the variability of the patient’s immune system response and the difficulty in identifying appropriate antigens for each patient. Despite these challenges, tumor microenvironment-targeted vaccine cancer therapies have shown promising results in preclinical and clinical studies and have the potential to become a valuable addition to current cancer treatment and “curative” options. While chemotherapeutic and monoclonal antibody treatments remain popular, ongoing research is needed to optimize the design and delivery of these therapies and to identify biomarkers that can predict response and guide patient selection. This comprehensive review explores the mechanisms of cancer vaccines, various delivery methods, and the role of adjuvants in improving treatment outcomes. It also discusses the historical background of cancer vaccine research and examines the current state of major cancer vaccination immunotherapies. Furthermore, the limitations and effectiveness of each vaccine type are analyzed, providing insights into the future of cancer vaccine development. Full article
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26 pages, 3421 KiB  
Review
CAR T Cell Locomotion in Solid Tumor Microenvironment
by Duy T. Nguyen, Elizabeth Ogando-Rivas, Ruixuan Liu, Theodore Wang, Jacob Rubin, Linchun Jin, Haipeng Tao, William W. Sawyer, Hector R. Mendez-Gomez, Matthew Cascio, Duane A. Mitchell, Jianping Huang, W. Gregory Sawyer, Elias J. Sayour and Paul Castillo
Cells 2022, 11(12), 1974; https://doi.org/10.3390/cells11121974 - 20 Jun 2022
Cited by 18 | Viewed by 7522
Abstract
The promising outcomes of chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies potentiates its capability in the fight against many cancers. Nevertheless, this immunotherapy modality needs significant improvements for the treatment of solid tumors. Researchers have incrementally identified limitations and constantly [...] Read more.
The promising outcomes of chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies potentiates its capability in the fight against many cancers. Nevertheless, this immunotherapy modality needs significant improvements for the treatment of solid tumors. Researchers have incrementally identified limitations and constantly pursued better CAR designs. However, even if CAR T cells are armed with optimal killer functions, they must overcome and survive suppressive barriers imposed by the tumor microenvironment (TME). In this review, we will discuss in detail the important role of TME in CAR T cell trafficking and how the intrinsic barriers contribute to an immunosuppressive phenotype and cancer progression. It is of critical importance that preclinical models can closely recapitulate the in vivo TME to better predict CAR T activity. Animal models have contributed immensely to our understanding of human diseases, but the intensive care for the animals and unreliable representation of human biology suggest in vivo models cannot be the sole approach to CAR T cell therapy. On the other hand, in vitro models for CAR T cytotoxic assessment offer valuable insights to mechanistic studies at the single cell level, but they often lack in vivo complexities, inter-individual heterogeneity, or physiologically relevant spatial dimension. Understanding the advantages and limitations of preclinical models and their applications would enable more reliable prediction of better clinical outcomes. Full article
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15 pages, 3330 KiB  
Review
Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells
by Pravin B. Sehgal
Cells 2022, 11(7), 1164; https://doi.org/10.3390/cells11071164 - 30 Mar 2022
Cited by 9 | Viewed by 3563
Abstract
It was recognized over 30 years ago that the polyfunctional cytokine interleukin-6 (IL-6) was an almost invariant presence at the host-tumor interface. The IL-6 in the tumor microenvironment was produced either by the cancer cell or by host stromal cells, or by tumor-infiltrating [...] Read more.
It was recognized over 30 years ago that the polyfunctional cytokine interleukin-6 (IL-6) was an almost invariant presence at the host-tumor interface. The IL-6 in the tumor microenvironment was produced either by the cancer cell or by host stromal cells, or by tumor-infiltrating immune cells, or all of them. IL-6 effects in this context included local changes in tumor cell-cell and cell-substrate adhesion, enhanced motility, epithelial to mesenchymal transformation (EMT), and changes in cell proliferation rates in both solid tumors as well as hematologic dyscrasias. Locally produced IL-6 enhanced cancer-targeting functions of tumor-infiltrating macrophages and immune cells. Additionally, the sex-biased phenotype of certain cancers [e.g., hepatocellular carcinoma (HCC) which is 3-5-fold more common in men] was related to the inhibition of macrophage-derived IL-6 production by estradiol-17β (E2). In many circumstances, locally produced IL-6 reached the peripheral circulation and elicited systemic effects such as cachexia and paraneoplastic syndrome (including fever, increased erythrocyte sedimentation rate, increased levels of C-reactive protein in serum, hypoalbuminemia). This review highlights the EMT produced by IL-6 in cancer cells, as well as mechanisms underlying sex bias in HCC, enhanced IL-6 expression in cancer cells resulting from mutations in p53, consequent alterations in STAT3 transcriptional signaling, and the newer understanding of STAT3 nuclear bodies in the cancer cell as phase-separated biomolecular condensates and membraneless organelles (MLOs). Moreover, the perplexing issue of discrepant measurements of IL-6 in human circulation using different assays, especially in patients undergoing immunotherapy, is discussed. Additionally, the paradoxical chaperone (enhancing) effect of anti-IL-6 “neutralizing” antibodies on IL-6 in vivo and consequent limitations of immunotherapy using anti-IL-6 mAb is considered. Full article
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