Editorial

3 pages, 180 KiB

Open AccessEditorial

Advancing Cancer Immunotherapy: From Molecular Mechanisms to Clinical Applications

by Xianda Zhao, Timothy Starr and Subbaya Subramanian

Cancers 2023, 15(16), 4197; https://doi.org/10.3390/cancers15164197 - 21 Aug 2023

Cited by 1 | Viewed by 1100

In recent years, cancer immunotherapy research has made remarkable progress, completely transforming the cancer treatment landscape [...] Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

Research

Jump to: Editorial, Review

22 pages, 5006 KiB

Open AccessArticle

Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells

by Thomas J. Gerton, Allen Green, Marco Campisi, Minyue Chen, Iliana Gjeci, Navin Mahadevan, Catherine A. A. Lee, Ranjan Mishra, Ha V. Vo, Koji Haratani, Ze-Hua Li, Kathleen T. Hasselblatt, Bryanna Testino, Trevor Connor, Christine G. Lian, Kevin M. Elias, Patrick Lizotte, Elena V. Ivanova, David A. Barbie and Daniela M. Dinulescu

Cancers 2023, 15(16), 4128; https://doi.org/10.3390/cancers15164128 - 16 Aug 2023

Cited by 2 | Viewed by 1522

Abstract

High-grade serous ovarian cancer (HGSOC) is responsible for the majority of gynecology cancer-related deaths. Patients in remission often relapse with more aggressive forms of disease within 2 years post-treatment. Alternative immuno-oncology (IO) strategies, such as immune checkpoint blockade (ICB) targeting the PD-(L)1 signaling [...] Read more.

High-grade serous ovarian cancer (HGSOC) is responsible for the majority of gynecology cancer-related deaths. Patients in remission often relapse with more aggressive forms of disease within 2 years post-treatment. Alternative immuno-oncology (IO) strategies, such as immune checkpoint blockade (ICB) targeting the PD-(L)1 signaling axis, have proven inefficient so far. Our aim is to utilize epigenetic modulators to maximize the benefit of personalized IO combinations in ex vivo 3D patient-derived platforms and in vivo syngeneic models. Using patient-derived tumor ascites, we optimized an ex vivo 3D screening platform (PDOTS), which employs autologous immune cells and circulating ascites-derived tumor cells, to rapidly test personalized IO combinations. Most importantly, patient responses to platinum chemotherapy and poly-ADP ribose polymerase inhibitors in 3D platforms recapitulate clinical responses. Furthermore, similar to clinical trial results, responses to ICB in PDOTS tend to be low and positively correlated with the frequency of CD3+ immune cells and EPCAM+/PD-L1+ tumor cells. Thus, the greatest response observed with anti-PD-1/anti-PD-L1 immunotherapy alone is seen in patient-derived HGSOC ascites, which present with high levels of systemic CD3+ and PD-L1+ expression in immune and tumor cells, respectively. In addition, priming with epigenetic adjuvants greatly potentiates ICB in ex vivo 3D testing platforms and in vivo tumor models. We further find that epigenetic priming induces increased tumor secretion of several key cytokines known to augment T and NK cell activation and cytotoxicity, including IL-6, IP-10 (CXCL10), KC (CXCL1), and RANTES (CCL5). Moreover, epigenetic priming alone and in combination with ICB immunotherapy in patient-derived PDOTS induces rapid upregulation of CD69, a reliable early activation of immune markers in both CD4+ and CD8+ T cells. Consequently, this functional precision medicine approach could rapidly identify personalized therapeutic combinations able to potentiate ICB, which is a great advantage, especially given the current clinical difficulty of testing a high number of potential combinations in patients. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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13 pages, 1194 KiB

Open AccessArticle

A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin’s Lymphoma

by Walter Hanel, Polina Shindiapina, David A. Bond, Yazeed Sawalha, Narendranath Epperla, Timothy Voorhees, Rina Li Welkie, Ying Huang, Gregory K. Behbehani, Xiaoli Zhang, Eric McLaughlin, Wing K. Chan, Jonathan E. Brammer, Samantha Jaglowski, John C. Reneau, Beth A. Christian, Basem M. William, Jonathon B. Cohen, Robert A. Baiocchi, Kami Maddocks, Kristie A. Blum and Lapo Alinari Show full author list Hide full author list

Cancers 2023, 15(5), 1437; https://doi.org/10.3390/cancers15051437 - 24 Feb 2023

Cited by 4 | Viewed by 2198

Abstract

Background: Relapsed or refractory classical Hodgkin lymphoma (cHL) remains a difficult treatment challenge. Although checkpoint inhibitors (CPI) have provided clinical benefit for these patients, responses are generally not durable, and progression eventually occurs. Discovering combination therapies which maximize the immune response of CPI [...] Read more.

Background: Relapsed or refractory classical Hodgkin lymphoma (cHL) remains a difficult treatment challenge. Although checkpoint inhibitors (CPI) have provided clinical benefit for these patients, responses are generally not durable, and progression eventually occurs. Discovering combination therapies which maximize the immune response of CPI therapy may overcome this limitation. We hypothesized that adding ibrutinib to nivolumab will lead to deeper and more durable responses in cHL by promoting a more favorable immune microenvironment leading to enhanced T-cell-mediated anti-lymphoma responses. Methods: We conducted a single arm, phase II clinical trial testing the efficacy of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who had received at least one prior line of therapy. Prior treatment with CPIs was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for up to 16 cycles. The primary objective was complete response rate (CRR) assessed per Lugano criteria. Secondary objectives included overall response rate (ORR), safety, progression free survival (PFS), and duration of response (DoR). Results: A total of 17 patients from two academic centers were enrolled. The median age of all patients was 40 (range 20–84). The median number of prior lines of treatment was five (range 1–8), including 10 patients (58.8%) who had progressed on prior nivolumab therapy. Most treatment related events were mild (<Grade 3) and expected from the individual side effect profiles of ibrutinib and nivolumab. In the intent to treat population (n = 17), the ORR and CRR were 51.9% (9/17) and 29.4% (5/17), which did not meet the prespecified efficacy endpoint of a CRR of 50%. In patients who received prior nivolumab therapy (n = 10), the ORR and CRR were 50.0% (5/10) and 20.0% (2/10), respectively. At a median follow up of 8.9 months, the median PFS was 17.3 months, and the median DOR was 20.2 months. There was no statistically significant difference in median PFS between patients who received previous nivolumab therapy versus patients who were nivolumab naïve (13.2 months vs. 22.0 months, p = 0.164). Conclusions: Combined nivolumab and ibrutinib led to a CRR of 29.4% in R/R cHL. Although this study did not meet its primary efficacy endpoint of a CRR of 50%, likely due to enrollment of heavily pretreated patients including over half of who had progressed on prior nivolumab treatment, responses that were achieved with combination ibrutinib and nivolumab therapy tended to be durable even in the case of prior progression on nivolumab therapy. Larger studies investigating the efficacy of dual BTK inhibitor/immune checkpoint blockade, particularly in patients who had previously progressed on checkpoint blockade therapy, are warranted. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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12 pages, 2610 KiB

Open AccessArticle

CD8+ Cell Density Gradient across the Tumor Epithelium–Stromal Interface of Non-Muscle Invasive Papillary Urothelial Carcinoma Predicts Recurrence-Free Survival after BCG Immunotherapy

by Julius Drachneris, Allan Rasmusson, Mindaugas Morkunas, Mantas Fabijonavicius, Albertas Cekauskas, Feliksas Jankevicius and Arvydas Laurinavicius

Cancers 2023, 15(4), 1205; https://doi.org/10.3390/cancers15041205 - 14 Feb 2023

Cited by 3 | Viewed by 1852

Abstract

Background: Bacille Calmette–Guerin (BCG) immunotherapy is the first-line treatment in patients with high-risk non-muscle invasive papillary urothelial carcinoma (NMIPUC), the most common type of bladder cancer. The therapy outcomes are variable and may depend on the immune response within the tumor microenvironment. In [...] Read more.

Background: Bacille Calmette–Guerin (BCG) immunotherapy is the first-line treatment in patients with high-risk non-muscle invasive papillary urothelial carcinoma (NMIPUC), the most common type of bladder cancer. The therapy outcomes are variable and may depend on the immune response within the tumor microenvironment. In our study, we explored the prognostic value of CD8+ cell density gradient indicators across the tumor epithelium–stroma interface of NMIPUC. Methods: Clinical and pathologic data were retrospectively collected from 157 NMIPUC patients treated with BCG immunotherapy after transurethral resection. Whole-slide digital image analysis of CD8 immunohistochemistry slides was used for tissue segmentation, CD8+ cell quantification, and the assessment of CD8+ cell densities within the epithelium–stroma interface. Subsequently, the gradient indicators (center of mass and immunodrop) were computed to represent the density gradient across the interface. Results: By univariable analysis of the clinicopathologic factors, including the history of previous NMIPUC, poor tumor differentiation, and pT1 stage, were associated with shorter RFS (p < 0.05). In CD8+ analyses, only the gradient indicators but not the absolute CD8+ densities were predictive for RFS (p < 0.05). The best-performing cross-validated model included previous episodes of NMIPUC (HR = 4.4492, p = 0.0063), poor differentiation (HR = 2.3672, p = 0.0457), and immunodrop (HR = 5.5072, p = 0.0455). Conclusions: We found that gradient indicators of CD8+ cell densities across the tumor epithelium–stroma interface, along with routine clinical and pathology data, improve the prediction of RFS in NMIPUC. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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14 pages, 5554 KiB

Open AccessArticle

A Case Study of Chimeric Antigen Receptor T Cell Function: Donor Therapeutic Differences in Activity and Modulation with Verteporfin

by Jiyong Liang, Dexing Fang, Joy Gumin, Hinda Najem, Moloud Sooreshjani, Renduo Song, Aria Sabbagh, Ling-Yuan Kong, Joseph Duffy, Irina V. Balyasnikova, Seth M. Pollack, Vinay K. Puduvalli and Amy B. Heimberger

Cancers 2023, 15(4), 1085; https://doi.org/10.3390/cancers15041085 - 08 Feb 2023

Cited by 2 | Viewed by 1754

Abstract

Background: Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought [...] Read more.

Background: Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the importance of this effect in epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells targeting glioma. Methods: EGFRvIII-specific CAR T cells were generated from various donors and analyzed for cytotoxicity, trogocytosis, and in vivo therapeutic activity against intracranial glioma. Tumor autophagy resulting from CAR T cell activity was evaluated in combination with an autophagy inducer (verteporfin) or inhibitor (bafilomycin A1). Results: CAR T cell products derived from different donors induced markedly divergent levels of trogocytosis of tumor antigen as well as PD-L1 upon engaging target tumor cells correlating with variability in efficacy in mice. Pharmacological facilitation of CAR induced-autophagy with verteporfin inhibits trogocytic expression of tumor antigen on CARs and increases CAR persistence and efficacy in mice. Conclusion: These data propose CAR-induced autophagy as a mechanism counteracting CAR-induced trogocytosis and provide a new strategy to innovate high-performance CARs through pharmacological facilitation of T cell-induced tumor death. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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19 pages, 4979 KiB

Open AccessArticle

Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models

by Sascha Troschke-Meurer, Maxi Zumpe, Lena Meißner, Nikolai Siebert, Piotr Grabarczyk, Hannes Forkel, Claudia Maletzki, Sander Bekeschus and Holger N. Lode

Cancers 2023, 15(3), 904; https://doi.org/10.3390/cancers15030904 - 31 Jan 2023

Cited by 4 | Viewed by 1880

Abstract

Anti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase. We investigated chemotherapeutic compounds used in newly diagnosed patients in combination with DB. Vincristine, etoposide, carboplatin, cisplatin, and cyclophosphamide, as well as DB, [...] Read more.

Anti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase. We investigated chemotherapeutic compounds used in newly diagnosed patients in combination with DB. Vincristine, etoposide, carboplatin, cisplatin, and cyclophosphamide, as well as DB, were used at concentrations achieved in pediatric clinical trials. The effects on stress ligand and checkpoint expression by neuroblastoma cells and on activation receptors of NK cells were determined by using flow cytometry. NK-cell activity was measured with a CD107a/IFN-γ assay. Long-term cytotoxicity was analyzed in three spheroid models derived from GD2-positive neuroblastoma cell lines (LAN-1, CHLA 20, and CHLA 136) expressing a fluorescent near-infrared protein. Chemotherapeutics combined with DB in the presence of immune cells improved cytotoxic efficacy up to 17-fold compared to in the controls, and the effect was GD2-specific. The activating stress and inhibitory checkpoint ligands on neuroblastoma cells were upregulated by the chemotherapeutics up to 9- and 5-fold, respectively, and activation receptors on NK cells were not affected. The CD107a/IFN-γ assay revealed no additional activation of NK cells by the chemotherapeutics. The synergistic effect of DB with chemotherapeutics seems primarily attributed to the combined toxicity of antibody-dependent cellular cytotoxicity and chemotherapy, which supports further clinical evaluation in frontline induction therapy. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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15 pages, 2353 KiB

Open AccessArticle

Characterization of Estrogen Receptors in Pancreatic Adenocarcinoma with Tertiary Lymphoid Structures

by Xuan Zou, Yu Liu, Xuan Lin, Ruijie Wang, Zhengjie Dai, Yusheng Chen, Mingjian Ma, Yesiboli Tasiheng, Yu Yan, Xu Wang, Xianjun Yu, He Cheng and Chen Liu

Cancers 2023, 15(3), 828; https://doi.org/10.3390/cancers15030828 - 29 Jan 2023

Cited by 3 | Viewed by 1962

Abstract

The role of estrogen signaling in antitumor immunology remains unknown for non-traditional sex-biased cancer types such as pancreatic adenocarcinoma (PAAD). Tertiary lymphoid structures (TLS) are active zones composed of multiple types of immune cells, whose presence indicates anti-tumor immune responses. In this study, [...] Read more.

The role of estrogen signaling in antitumor immunology remains unknown for non-traditional sex-biased cancer types such as pancreatic adenocarcinoma (PAAD). Tertiary lymphoid structures (TLS) are active zones composed of multiple types of immune cells, whose presence indicates anti-tumor immune responses. In this study, we employed a 12-chemokine signature to characterize potential gene categories associated with TLS development and identified seventeen major gene categories including estrogen receptors (ERs). Immunohistochemistry staining revealed the expression patterns of three ERs (ERα, ERβ, and GPER) in 174 PAAD samples, and their correlation with clinicopathological characteristics, immune cell infiltration levels, and intratumoral TLS presence was analyzed. The results indicated that ERα (+) and ERβ (+) were correlated with high tumor grade, and ERβ (+) and GPER (+) were correlated with lower TNM stage, and both ERα (+) and GPER (+) displayed a beneficial effect on prognosis in this cohort. Interestingly, positive staining of all three ERs was significantly correlated with the presence of intratumoral TLSs and infiltration of more active immune cells into the microenvironment. Moreover, the chemotaxis of CD8⁺T-cells to PAAD cells was significantly increased in vitro with upregulated expression of ERα or ERβ on PAAD cells. To conclude, our study showed a novel correlation between ER expression and TLS development, suggesting that ERs may play a protective role by enhancing anti-tumor immune responses in PAAD. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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18 pages, 1790 KiB

Open AccessArticle

The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD₂ Antibody Dinutuximab Beta

by Nikolai Siebert, Justus Leopold, Maxi Zumpe, Sascha Troschke-Meurer, Simon Biskupski, Alexander Zikoridse and Holger N. Lode

Cancers 2022, 14(19), 4842; https://doi.org/10.3390/cancers14194842 - 04 Oct 2022

Cited by 6 | Viewed by 1869

Abstract

Treatment of high-risk neuroblastoma (NB) patients with the anti-GD₂ antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity (ADCC) is the major mechanism of action and is primarily mediated by NK cells. Since IL-2 co-treatment did not show a [...] Read more.

Treatment of high-risk neuroblastoma (NB) patients with the anti-GD₂ antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity (ADCC) is the major mechanism of action and is primarily mediated by NK cells. Since IL-2 co-treatment did not show a therapeutic benefit but strongly induced Treg, we investigated here a DB-based immunotherapy combined with the immunocytokine FAP-IL-2v, which comprises a fibroblast activation protein α (FAP)-specific Ab linked to a mutated IL-2 variant (IL-2v) with abolished binding to the high-affinity IL-2 receptor, thus stimulating NK cells without induction of Treg. Effects of FAP-IL-2v on NK cells, Treg and ADCC mediated by DB, as well as FAP expression in NB, were investigated by flow cytometry, calcein-AM-based cytotoxicity assay and RT-PCR analysis. Moreover, the impact of soluble factors released from tumor cells on FAP expression by primary fibroblasts was assessed. Finally, a combined immunotherapy with DB and FAP-IL-2v was evaluated using a resistant syngeneic murine NB model. Incubation of leukocytes with FAP-IL-2v enhanced DB-specific ADCC without induction of Treg. FAP expression on NB cells and myeloid-derived suppressor cells (MDCS) in tumor tissue was identified. A tumor-cell-dependent enhancement in FAP expression by primary fibroblasts was demonstrated. Combination with DB and FAP-IL-2v resulted in reduced tumor growth and improved survival. Analysis of tumor tissue revealed increased NK and cytotoxic T cell numbers and reduced Treg compared to controls. Our data show that FAP-IL-2v is a potent immunocytokine that augments the efficacy of DB against NB, providing a promising alternative to IL-2. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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15 pages, 3850 KiB

Open AccessArticle

Reversing PD-1 Resistance in B16F10 Cells and Recovering Tumour Immunity Using a COX2 Inhibitor

by Chenyu Pi, Ping Jing, Bingyu Li, Yan Feng, Lijun Xu, Kun Xie, Tao Huang, Xiaoqing Xu, Hua Gu and Jianmin Fang

Cancers 2022, 14(17), 4134; https://doi.org/10.3390/cancers14174134 - 26 Aug 2022

Cited by 9 | Viewed by 2799

Abstract

Immunotherapy is an effective method for tumour treatment. Anti-programmed cell death protein 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) monoclonal antibodies play a significant role in immunotherapy of most tumours; however, some patients develop drug resistance to PD-1/PD-L1 therapy. Cyclooxygenase-2 (COX2) is expressed [...] Read more.

Immunotherapy is an effective method for tumour treatment. Anti-programmed cell death protein 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) monoclonal antibodies play a significant role in immunotherapy of most tumours; however, some patients develop drug resistance to PD-1/PD-L1 therapy. Cyclooxygenase-2 (COX2) is expressed in various solid tumours, and prostaglandin E2 (PGE2) drives the development of malignant tumours. We developed a drug-resistant B16F10 (B16F10-R) tumour mouse model through four rounds of selection in vivo. Subsequently, we investigated changes in PD-L1 expression and lymphocyte infiltration in B16F10-NR and B16F10-R tumours. Additionally, we explored the role of COX2 in acquired resistance to pembrolizumab, an anti-PD-1 treatment. Immune cell infiltration was significantly decreased in resistant tumours compared to B16F10-NR tumours; however, ptgs2 gene expression was significantly elevated in resistant tumours. Aspirin or celecoxib combined with pembrolizumab can effectively reverse tumour drug resistance. In addition, ptgs2 knockout or the use of the EP4 inhibitor E7046 abrogated drug resistance to anti-PD-1 treatment in B16F10-R tumour cells. Our study showed that inhibition of the COX2/PGE2/EP4 axis could increase the number of immune cells infiltrating the tumour microenvironment and recover drug-resistant tumour sensitivity to pembrolizumab. Thus, we highlight COX2 inhibition as a promising therapeutic target for drug-resistant tumours for future consideration. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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Review

Jump to: Editorial, Research

18 pages, 1922 KiB

Open AccessReview

Metabolic Barriers to Glioblastoma Immunotherapy

by Nikita Choudhary, Robert C. Osorio, Jun Y. Oh and Manish K. Aghi

Cancers 2023, 15(5), 1519; https://doi.org/10.3390/cancers15051519 - 28 Feb 2023

Cited by 4 | Viewed by 1954

Abstract

Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been [...] Read more.

Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients (glucose, glutamine, tryptophan, and lipids) has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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12 pages, 593 KiB

Open AccessReview

Targeted Therapy of Interleukin-34 as a Promising Approach to Overcome Cancer Therapy Resistance

by Giovanni Monteleone, Eleonora Franzè, Claudia Maresca, Marco Colella, Teresa Pacifico and Carmine Stolfi

Cancers 2023, 15(3), 971; https://doi.org/10.3390/cancers15030971 - 03 Feb 2023

Cited by 4 | Viewed by 2047

Abstract

Chemotherapy and immunotherapy have markedly improved the management of several malignancies. However, not all cancer patients respond primarily to such therapies, and others can become resistant during treatment. Thus, identification of the factors/mechanisms underlying cancer resistance to such treatments could help develop novel [...] Read more.

Chemotherapy and immunotherapy have markedly improved the management of several malignancies. However, not all cancer patients respond primarily to such therapies, and others can become resistant during treatment. Thus, identification of the factors/mechanisms underlying cancer resistance to such treatments could help develop novel effective therapeutic compounds. Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) are major components of the suppressive tumor microenvironment and are critical drivers of immunosuppression, creating a tumor-promoting and drug-resistant niche. In this regard, therapeutic strategies to tackle immunosuppressive cells are an interesting option to increase anti-tumor immune responses and overcome the occurrence of drug resistance. Accumulating evidence indicates that interleukin-34 (IL-34), a cytokine produced by cancer cells, and/or TAMs act as a linker between induction of a tumor-associated immunosuppressive microenvironment and drug resistance. In this article, we review the current data supporting the role of IL-34 in the differentiation/function of immune suppressive cells and, hence, in the mechanisms leading to therapeutic resistance in various cancers. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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26 pages, 444 KiB

Open AccessReview

Interactions between Dietary Micronutrients, Composition of the Microbiome and Efficacy of Immunotherapy in Cancer Patients

by Małgorzata Frąk, Anna Grenda, Paweł Krawczyk, Janusz Milanowski and Ewa Kalinka

Cancers 2022, 14(22), 5577; https://doi.org/10.3390/cancers14225577 - 14 Nov 2022

Cited by 4 | Viewed by 1676

Abstract

The effectiveness of immunotherapy in cancer patients depends on the activity of the host’s immune system. The intestinal microbiome is a proven immune system modulator, which plays an important role in the development of many cancers and may affect the effectiveness of anti-cancer [...] Read more.

The effectiveness of immunotherapy in cancer patients depends on the activity of the host’s immune system. The intestinal microbiome is a proven immune system modulator, which plays an important role in the development of many cancers and may affect the effectiveness of anti-cancer therapy. The richness of certain bacteria in the gut microbiome (e.g., Bifidobacterium spp., Akkermanisa muciniphila and Enterococcus hire) improves anti-tumor specific immunity and the response to anti-PD-1 or anti-PD-L1 immunotherapy by activating antigen-presenting cells and cytotoxic T cells within the tumor. Moreover, micronutrients affect directly the activities of the immune system or regulate their function by influencing the composition of the microbiome. Therefore, micronutrients can significantly influence the effectiveness of immunotherapy and the development of immunorelated adverse events. In this review, we describe the relationship between the supply of microelements and the abundance of various bacteria in the intestinal microbiome and the effectiveness of immunotherapy in cancer patients. We also point to the function of the immune system in the case of shifts in the composition of the microbiome and disturbances in the supply of microelements. This may in the future become a therapeutic target supporting the effects of immunotherapy in cancer patients. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

29 pages, 6253 KiB

Open AccessReview

Recent Advances in Bacteria-Based Cancer Treatment

by Xianyuan Wei, Meng Du, Zhiyi Chen and Zhen Yuan

Cancers 2022, 14(19), 4945; https://doi.org/10.3390/cancers14194945 - 09 Oct 2022

Cited by 9 | Viewed by 3499

Abstract

Owing to its unique mechanism of abundant pathogen-associated molecular patterns in antitumor immune responses, bacteria-based cancer immunotherapy has recently attracted wide attention. Compared to traditional cancer treatments such as surgery, chemotherapy, radiotherapy, and phototherapy, bacteria-based cancer immunotherapy exhibits the versatile capabilities for suppressing [...] Read more.

Owing to its unique mechanism of abundant pathogen-associated molecular patterns in antitumor immune responses, bacteria-based cancer immunotherapy has recently attracted wide attention. Compared to traditional cancer treatments such as surgery, chemotherapy, radiotherapy, and phototherapy, bacteria-based cancer immunotherapy exhibits the versatile capabilities for suppressing cancer thanks to its preferentially accumulating and proliferating within tumors. In particular, bacteria have demonstrated their anticancer effect through the toxins, and other active components from the cell membrane, cell wall, and dormant spores. More importantly, the design of engineering bacteria with detoxification and specificity is essential for the efficacy of bacteria-based cancer therapeutics. Meanwhile, bacteria can deliver the cytokines, antibody, and other anticancer theranostic nanoparticles to tumor microenvironments by regulating the expression of the bacterial genes or chemical and physical loading. In this review, we illustrate that naïve bacteria and their components can serve as robust theranostic agents for cancer eradication. In addition, we summarize the recent advances in efficient antitumor treatments by genetically engineering bacteria and bacteria-based nanoparticles. Further, possible future perspectives in bacteria-based cancer immunotherapy are also inspected. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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13 pages, 780 KiB

Open AccessReview

Immunotherapy of Neuroendocrine Neoplasms: Any Role for the Chimeric Antigen Receptor T Cells?

by Giuseppe Fanciulli, Roberta Modica, Anna La Salvia, Federica Campolo, Tullio Florio, Nevena Mikovic, Alice Plebani, Valentina Di Vito, Annamaria Colao and Antongiulio Faggiano

Cancers 2022, 14(16), 3991; https://doi.org/10.3390/cancers14163991 - 18 Aug 2022

Cited by 9 | Viewed by 2214

Abstract

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with variable clinical presentation and prognosis. Surgery, when feasible, is the most effective and often curative treatment. However, NENs are frequently locally advanced or already metastatic at diagnosis. Consequently, additional local or systemic therapeutic [...] Read more.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with variable clinical presentation and prognosis. Surgery, when feasible, is the most effective and often curative treatment. However, NENs are frequently locally advanced or already metastatic at diagnosis. Consequently, additional local or systemic therapeutic approaches are required. Immunotherapy, based on chimeric antigen receptor T cells (CAR-T), is showing impressive results in several cancer treatments. The aim of this narrative review is to analyze the available data about the use of CAR-T in NENs, including studies in both preclinical and clinical settings. We performed an extensive search for relevant data sources, comprising full-published articles, abstracts from international meetings, and worldwide registered clinical trials. Preclinical studies performed on both cell lines and animal models indicate a significant therapeutic effect of CAR-T cells in NENs. Ongoing and future clinical trials will clarify the possible role of these drugs in patients with highly aggressive NENs. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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