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Molecular Basis and Advances of Targeted Immunotherapy for Cancer
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Molecular Basis and Advances of Targeted Immunotherapy for Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 20194

Special Issue Editors

Prof. Dr. Antonio Maccio

E-Mail Website
Guest Editor
1. Department of Gynecologic Oncology, ARNAS G.Brotzu, 09124 Cagliari, Italy
2. Department of Surgical Sciences, University of Cagliari, 09124 Cagliari, Italy
Interests: ovarian cancer; laparoscopic surgery; immune system and immunotherapy; inflammation; macrophages; cytokines; cancer cachexia; cancer-related anemia
Special Issues, Collections and Topics in MDPI journals
Dr. Clelia Madeddu

E-Mail Website
Guest Editor
Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
Interests: oncology; drug

Special Issue Information

Dear Colleagues,

Cancer cells can be considered pathogens; therefore, their related pathology depends on the tumor growth extent and the effectiveness of the immune system response. The immune response against cancer can be divided into two phases. The initial phase is called resistance, where the body tries to get rid of cancer cells, and the second is called tolerance, where the body attempts to limit the health impact caused by cancer. The clinical manifestation of cancer highlights the low tumor immunogenicity and the reduced ability of the immune system to control tumor cell growth due to escape mechanisms. The activation of the immune system, known as immunosurveillance, follows the classical steps of antigen recognition, antigen presentation to effector and regulatory T cells, and the physiological end of the immune response through immune checkpoint pathways. For a long time, researchers have tried to stimulate the immune system of cancer patients to use it as a therapeutic strategy. During these attempts, the mechanisms of immune escape have emerged and been better defined, thus identifying new classes of immunotherapy drugs as immuno-checkpoint inhibitors. The use of next-generation sequencing and molecular analysis may be fundamental to identify predictive biomarkers of response/resistance to immune checkpoint inhibitors, as a prelude to the development of rational treatment strategy. The identification of predictive markers for immunotherapy is evolving. In fact, PD-L1 expression in tumors is recognized as an eligibility criterion for immunotherapy, although not univocally. Other gene mutations, especially those involved in mismatch repair (MMR), may predict the efficacy of immunotherapy. Mutations in MMR genes impair DNA repair, which can lead to microsatellite instability that is associated with neo-antigen formation. Mutations in DNA repair and replication genes have been associated with a higher mutational load and correlated with increased response to the PD-1 blockade.

This Special Issue aims to discuss innovative biomolecular mechanisms that may represent the rationale for new targeted therapeutic strategies able to improve the response to immunotherapy in cancer patients. It welcomes original research, reviews, and short communication articles mainly focused on the molecular basis and advances in cancer immunotherapy.

Prof. Dr. Antonio Maccio
Prof. Dr. Clelia Madeddu
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • immunotherapy
  • resistance
  • tolerance
  • macrophage
  • inflammation
  • immune checkpoint inhibitors
  • molecular profile
  • next-generation sequencing
  • PD-1
  • microenvironment
  • genome sequencing
  • mutational load

Published Papers (7 papers)

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Editorial

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4 pages, 204 KiB  
Editorial
Molecular Basis and Advances in Targeted Immunotherapy for Cancer
by Antonio Macciò and Clelia Madeddu
Int. J. Mol. Sci. 2023, 24(9), 7802; https://doi.org/10.3390/ijms24097802 - 25 Apr 2023
Cited by 1 | Viewed by 969
Abstract
Researchers have long attempted to stimulate the immune system of cancer patients as a therapeutic strategy [...] Full article
(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Immunotherapy for Cancer)

Research

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22 pages, 7630 KiB  
Article
Development of a Hallmark Pathway-Related Gene Signature Associated with Immune Response for Lower Grade Gliomas
by Guichuan Lai, Xiaoni Zhong, Hui Liu, Jielian Deng, Kangjie Li and Biao Xie
Int. J. Mol. Sci. 2022, 23(19), 11971; https://doi.org/10.3390/ijms231911971 - 09 Oct 2022
Cited by 15 | Viewed by 1923
Abstract
Although some biomarkers have been used to predict prognosis of lower-grade gliomas (LGGs), a pathway-related signature associated with immune response has not been developed. A key signaling pathway was determined according to the lowest adjusted p value among 50 hallmark pathways. The least [...] Read more.
Although some biomarkers have been used to predict prognosis of lower-grade gliomas (LGGs), a pathway-related signature associated with immune response has not been developed. A key signaling pathway was determined according to the lowest adjusted p value among 50 hallmark pathways. The least absolute shrinkage and selection operator (LASSO) and stepwise multivariate Cox analyses were performed to construct a pathway-related gene signature. Somatic mutation, drug sensitivity and prediction of immunotherapy analyses were conducted to reveal the value of this signature in targeted therapies. In this study, an allograft rejection (AR) pathway was considered as a crucial signaling pathway, and we constructed an AR-related five-gene signature, which can independently predict the prognosis of LGGs. High-AR LGG patients had higher tumor mutation burden (TMB), Immunophenscore (IPS), IMmuno-PREdictive Score (IMPRES), T cell-inflamed gene expression profile (GEP) score and MHC I association immunoscore (MIAS) than low-AR patients. Most importantly, our signature can be validated in four immunotherapy cohorts. Furthermore, IC50 values of the six classic chemotherapeutic drugs were significantly elevated in the low-AR group compared with the high-AR group. This signature might be regarded as an underlying biomarker in predicting prognosis for LGGs, possibly providing more therapeutic strategies for future clinical research. Full article
(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Immunotherapy for Cancer)
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27 pages, 2899 KiB  
Article
A Micro-Immunotherapy Sequential Medicine MIM-seq Displays Immunomodulatory Effects on Human Macrophages and Anti-Tumor Properties towards In Vitro 2D and 3D Models of Colon Carcinoma and in an In Vivo Subcutaneous Xenograft Colon Carcinoma Model
by Camille Jacques, Irene Marchesi, Francesco Paolo Fiorentino, Mathias Chatelais, Nicoletta Libera Lilli, Kurt Appel, Beatrice Lejeune and Ilaria Floris
Int. J. Mol. Sci. 2022, 23(11), 6059; https://doi.org/10.3390/ijms23116059 - 27 May 2022
Cited by 7 | Viewed by 2585
Abstract
In this study, the immunomodulatory effects of a sequential micro-immunotherapy medicine, referred as MIM-seq, were appraised in human primary M1 and M2 macrophages, in which the secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-12, IL-23, and tumor necrosis factor (TNF)-alpha, was [...] Read more.
In this study, the immunomodulatory effects of a sequential micro-immunotherapy medicine, referred as MIM-seq, were appraised in human primary M1 and M2 macrophages, in which the secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-12, IL-23, and tumor necrosis factor (TNF)-alpha, was inhibited. In addition, the potential anti-proliferative effects of MIM-seq on tumor cells was assessed in three models of colorectal cancer (CRC): an in vitro two-dimensions (2D) model of HCT-116 cells, an in vitro tri-dimensional (3D) model of spheroids, and an in vivo model of subcutaneous xenografted mice. In these models, MIM-seq displayed anti-proliferative effects when compared with the vehicle. In vivo, the tumor growth was slightly reduced in MIM-seq-treated animals. Moreover, MIM-seq could slightly reduce the growth of our spheroid models, especially under serum-deprivation. When MIM-seq was combined with two well-known anti-cancerogenic agents, either resveratrol or etoposide, MIM-seq could even further reduce the spheroid’s volume, pointing up the need to further assess whether MIM-seq could be beneficial for CRC patients as an adjuvant therapy. Altogether, these data suggest that MIM-seq could have anti-tumor properties against CRC and an immunomodulatory effect towards the mediators of inflammation, whose systemic dysregulation is considered to be a poor prognosis for patients. Full article
(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Immunotherapy for Cancer)
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Review

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23 pages, 1998 KiB  
Review
Extracellular Vesicles Are Important Mediators That Regulate Tumor Lymph Node Metastasis via the Immune System
by Yoshitaka Kiya, Yusuke Yoshioka, Yuichi Nagakawa and Takahiro Ochiya
Int. J. Mol. Sci. 2023, 24(2), 1362; https://doi.org/10.3390/ijms24021362 - 10 Jan 2023
Cited by 3 | Viewed by 2185
Abstract
Extracellular vesicles (EVs) are particles with a lipid bilayer structure, and they are secreted by various cells in the body. EVs interact with and modulate the biological functions of recipient cells by transporting their cargoes, such as nucleic acids and proteins. EVs influence [...] Read more.
Extracellular vesicles (EVs) are particles with a lipid bilayer structure, and they are secreted by various cells in the body. EVs interact with and modulate the biological functions of recipient cells by transporting their cargoes, such as nucleic acids and proteins. EVs influence various biological phenomena, including disease progression. They also participate in tumor progression by stimulating a variety of signaling pathways and regulating immune system activation. EVs induce immune tolerance by suppressing CD8+ T-cell activation or polarizing macrophages toward the M2 phenotype, which results in tumor cell proliferation, migration, invasion, and metastasis. Moreover, immune checkpoint molecules are also expressed on the surface of EVs that are secreted by tumors that express these molecules, allowing tumor cells to not only evade immune cell attack but also acquire resistance to immune checkpoint inhibitors. During tumor metastasis, EVs contribute to microenvironmental changes in distant organs before metastatic lesions appear; thus, EVs establish a premetastatic niche. In particular, lymph nodes are adjacent organs that are connected to tumor lesions via lymph vessels, so that tumor cells metastasize to draining lymph nodes at first, such as sentinel lymph nodes. When EVs influence the microenvironment of lymph nodes, which are secondary lymphoid tissues, the immune response against tumor cells is weakened; subsequently, tumor cells spread throughout the body. In this review, we will discuss the association between EVs and tumor progression via the immune system as well as the clinical application of EVs as biomarkers and therapeutic agents. Full article
(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Immunotherapy for Cancer)
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15 pages, 1298 KiB  
Review
Advances in Targeted Immunotherapy for Hepatobiliary Cancers
by Samantha M. Ruff, Alexander H. Shannon and Timothy M. Pawlik
Int. J. Mol. Sci. 2022, 23(22), 13961; https://doi.org/10.3390/ijms232213961 - 12 Nov 2022
Cited by 11 | Viewed by 2227
Abstract
Cancer of the hepatobiliary system can be divided into primary liver cancer and biliary tract cancer (BTC), which includes hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder cancer (GBC). These aggressive cancers often present at an advanced stage or among patients with poorly preserved [...] Read more.
Cancer of the hepatobiliary system can be divided into primary liver cancer and biliary tract cancer (BTC), which includes hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder cancer (GBC). These aggressive cancers often present at an advanced stage or among patients with poorly preserved liver function. The primary treatment for HCC and BTC when diagnosed early is surgical resection, but given the high rate of recurrence and often advanced stage at diagnosis, many patients will require systemic therapy. Unfortunately, even with systemic therapy, long-term survival is poor. The immune system plays an important role in preventing cancer progression. The unique immune environment of the liver and subsequent alterations to the immune microenvironment by tumor cells to create a favorable microenvironment plays a key role in the progression of HCC and BTC. Due to the paucity of effective systemic therapies and distinctive immune environment of the liver, research and clinical trials are investigating the use of immunotherapy in HCC and BTC. This review will focus on current immunotherapies and emerging data for the treatment of HCC and BTC. Full article
(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Immunotherapy for Cancer)
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16 pages, 1504 KiB  
Review
EGFR-Mutated Non-Small Cell Lung Cancer and Resistance to Immunotherapy: Role of the Tumor Microenvironment
by Clelia Madeddu, Clelia Donisi, Nicole Liscia, Eleonora Lai, Mario Scartozzi and Antonio Macciò
Int. J. Mol. Sci. 2022, 23(12), 6489; https://doi.org/10.3390/ijms23126489 - 10 Jun 2022
Cited by 45 | Viewed by 6526
Abstract
Lung cancer is a leading cause of cancer-related deaths worldwide. About 10–30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate [...] Read more.
Lung cancer is a leading cause of cancer-related deaths worldwide. About 10–30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate the antitumor immune response. EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape. EGFR-Tyrosine Kinase Inhibitors (TKIs) strengthen MHC class I and II antigen presentation in response to IFN-γ, boost CD8+ T-cells levels and DCs, eliminate FOXP3+ Tregs, inhibit macrophage polarization into the M2 phenotype, and decrease PD-L1 expression in cancer cells. Thus, targeted therapy blocks specific signaling pathways, whereas immunotherapy stimulates the immune system to attack tumor cells evading immune surveillance. A combination of TKIs and immunotherapy may have suboptimal synergistic effects. However, data are controversial because activated EGFR signaling allows NSCLC cells to use multiple strategies to create an immunosuppressive TME, including recruitment of Tumor-Associated Macrophages and Tregs and the production of inhibitory cytokines and metabolites. Therefore, these mechanisms should be characterized and targeted by a combined pharmacological approach that also concerns disease stage, cancer-related inflammation with related systemic symptoms, and the general status of the patients to overcome the single-drug resistance development. Full article
(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Immunotherapy for Cancer)
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Other

11 pages, 1858 KiB  
Case Report
Efficacy of Dabrafenib and Trametinib in a Patient with Squamous-Cell Carcinoma, with Mutation p.D594G in BRAF and p.R461* in NF1 Genes—A Case Report with Literature Review
by Anna Grenda, Pawel Krawczyk, Katarzyna M. Targowska-Duda, Robert Kieszko, Iwona Paśnik and Janusz Milanowski
Int. J. Mol. Sci. 2023, 24(2), 1195; https://doi.org/10.3390/ijms24021195 - 07 Jan 2023
Cited by 4 | Viewed by 2866
Abstract
The 3rd class of BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase) variants including G466, D594, and A581 mutations cause kinase death or impaired kinase activity. It is unlikely that RAF (Raf Proto-Oncogene, Serine/Threonine Kinase) inhibitors suppress ERK (Extracellular Signal-Regulated Kinase) signaling in class 3 mutant-driven [...] Read more.
The 3rd class of BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase) variants including G466, D594, and A581 mutations cause kinase death or impaired kinase activity. It is unlikely that RAF (Raf Proto-Oncogene, Serine/Threonine Kinase) inhibitors suppress ERK (Extracellular Signal-Regulated Kinase) signaling in class 3 mutant-driven tumors due to the fact that they preferentially inhibit activated BRAF V600 mutants. However, there are suggestions that class 3 mutations are still associated with enhanced RAS/MAPK (RAS Proto-Oncogene, GTPase/Mitogen-Activated Protein Kinase) activation, potentially due to other mechanisms such as the activation of growth factor signaling or concurrent MAPK pathway mutations, e.g., RAS or NF1 (Neurofibromin 1). A 75-year-old male patient with squamous-cell cancer (SqCC) of the lung and with metastases to the kidney and mediastinal lymph nodes received chemoimmunotherapy (expression of Programmed Cell Death 1 Ligand 1 (PD-L1) on 2% of tumor cells). The chemotherapy was limited due to the accompanying myelodysplastic syndrome (MDS), and pembrolizumab monotherapy was continued for up to seven cycles. At the time of progression, next-generation sequencing was performed and a c.1781A>G (p.Asp594Gly) mutation in the BRAF gene, a c.1381C>T (p.Arg461Ter) mutation in the NF1 gene, and a c.37C>T (p.Gln13Ter) mutation in the FANCC gene were identified. Combined therapy with BRAF (dabrafenib) and MEK (trametinib) inhibitors was used, which resulted in the achievement of partial remission of the primary lesion and lung nodules and the stabilization of metastatic lesions in the kidney and bones. The therapy was discontinued after five months due to myelosuppression associated with MDS. The molecular background was decisive for the patient’s fate. NSCLC patients with non-V600 mutations in the BRAF gene rarely respond to anti-BRAF and anti-MEK therapy. The achieved effectiveness of the treatment could be related to a mutation in the NF1 tumor suppressor gene. The loss of NF1 function causes the excessive activation of KRAS and overactivity of the signaling pathway containing BRAF and MEK, which were the targets of the therapy. Moreover, the mutation in the FANCC gene was probably related to MDS development. The NGS technique was crucial for the qualification to treatment and the prediction of the NSCLC course in our patient. The mutations in two genes—the BRAF oncogene and the NF1 tumor suppressor gene—were the reason for the use of dabrafenib and trametinib treatment. The patients achieved short-term disease stabilization. This proved that coexisting mutations in these genes affect the disease course and treatment efficacy. Full article
(This article belongs to the Special Issue Molecular Basis and Advances of Targeted Immunotherapy for Cancer)
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