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Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 22085

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Special Issue Editor

Dr. Jason Yongsheng Chan

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Guest Editor

Department of Medical Oncology, National Cancer Centre Singapore | NCCS, Singapore, Singapore
Interests: rare cancers; lymphoma; biomarkers; translational research; genomics; spatial technologies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The field of cancer immunotherapy continues to excite basic scientific and translational research. From an oncologist’s perspective, immunotherapy has revolutionized contemporary cancer management, and is now considered a standard treatment option for many types of cancer. However, a major unmet need exists in that treatment resistance occurs in the vast majority of patients. A deeper understanding of tumor-intrinsic factors and their interplay with the tumor microenvironment has led to the identification of potential biomarkers of resistance and response, and has opened new avenues to improve upon existing treatment approaches. Moving forwards, it is anticipated that emerging innovative technologies that enable multi-dimensional, high-throughput and multiplex profiling will drive new discoveries in this aspect.

I cordially invite authors to submit original research and review articles to this Special Issue, which addresses the latest progress in and current understanding of complex mechanisms underlying responses and resistance to cancer immunotherapy.

In this Special Issue, experts in the field will review the latest research on the tumor microenvironment and its role in modulating immune resistance across various cancer types. Additionally, the topics will cover broad mechanisms of immunotherapy resistance and novel strategies to overcome them. It will also encourage research articles related to new predictive biomarkers and emerging therapeutic targets, as well as state-of-the-art technologies that accelerate studies in these areas.

Dr. Jason Yongsheng Chan
Guest Editor

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

cancer immunotherapy
tumor microenvironment
biomarkers; immune resistance
T cells
immune checkpoint
tumor-infiltrating lymphocytes
tumor mutational burden
dendritic cells
PD-L1

Published Papers (9 papers)

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Research

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13 pages, 1771 KiB

Open AccessArticle

Hypoxia Is Associated with Increased Immune Infiltrates and Both Anti-Tumour and Immune Suppressive Signalling in Muscle-Invasive Bladder Cancer

by Vicky Smith, Dave Lee, Mark Reardon, Rekaya Shabbir, Sudhakar Sahoo, Peter Hoskin, Ananya Choudhury, Timothy Illidge and Catharine M. L. West

Int. J. Mol. Sci. 2023, 24(10), 8956; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108956 - 18 May 2023

Cited by 2 | Viewed by 1409

Abstract

Hypoxia and a suppressive tumour microenvironment (TME) are both independent negative prognostic factors for muscle-invasive bladder cancer (MIBC) that contribute to treatment resistance. Hypoxia has been shown to induce an immune suppressive TME by recruiting myeloid cells that inhibit anti-tumour T cell responses. Recent transcriptomic analyses show hypoxia increases suppressive and anti-tumour immune signalling and infiltrates in bladder cancer. This study sought to investigate the relationship between hypoxia-inducible factor (HIF)-1 and -2, hypoxia, and immune signalling and infiltrates in MIBC. ChIP-seq was performed to identify HIF1α, HIF2α, and HIF1β binding in the genome of the MIBC cell line T24 cultured in 1% and 0.1% oxygen for 24 h. Microarray data from four MIBC cell lines (T24, J82, UMUC3, and HT1376) cultured under 1%, 0.2%, and 0.1% oxygen for 24 h were used. Differences in the immune contexture between high- and low-hypoxia tumours were investigated using in silico analyses of two bladder cancer cohorts (BCON and TCGA) filtered to only include MIBC cases. GO and GSEA were used with the R packages “limma” and “fgsea”. Immune deconvolution was performed using ImSig and TIMER algorithms. RStudio was used for all analyses. Under hypoxia, HIF1α and HIF2α bound to ~11.5–13.5% and ~4.5–7.5% of immune-related genes, respectively (1–0.1% O₂). HIF1α and HIF2α both bound to genes associated with T cell activation and differentiation signalling pathways. HIF1α and HIF2α had distinct roles in immune-related signalling. HIF1 was associated with interferon production specifically, whilst HIF2 was associated with generic cytokine signalling as well as humoral and toll-like receptor immune responses. Neutrophil and myeloid cell signalling was enriched under hypoxia, alongside hallmark pathways associated with Tregs and macrophages. High-hypoxia MIBC tumours had increased expression of both suppressive and anti-tumour immune gene signatures and were associated with increased immune infiltrates. Overall, hypoxia is associated with increased inflammation for both suppressive and anti-tumour-related immune signalling and immune infiltrates, as seen in vitro and in situ using MIBC patient tumours. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance)

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11 pages, 664 KiB

Open AccessArticle

Circulating CD137⁺ T Cell Levels Are Correlated with Response to Pembrolizumab Treatment in Advanced Head and Neck Cancer Patients

by Alessio Cirillo, Ilaria Grazia Zizzari, Andrea Botticelli, Lidia Strigari, Hassan Rahimi, Simone Scagnoli, Fabio Scirocchi, Angelina Pernazza, Angelica Pace, Bruna Cerbelli, Giulia d’Amati, Paolo Marchetti, Marianna Nuti, Aurelia Rughetti and Chiara Napoletano

Int. J. Mol. Sci. 2023, 24(8), 7114; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087114 - 12 Apr 2023

Cited by 2 | Viewed by 1801

Abstract

Pembrolizumab, an anti-PD-1 antibody, has been approved as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma ((R/M) HNSCC). However, only a minority of patients benefit from immunotherapy, which highlights the need to identify novel biomarkers to optimize treatment strategies. CD137⁺ T cells have been identified as tumour-specific T cells correlated with immunotherapy responses in several solid tumours. In this study, we investigated the role of circulating CD137⁺ T cells in (R/M) HNSCC patients undergoing pembrolizumab treatment. PBMCs obtained from 40 (R/M) HNSCC patients with a PD-L1 combined positive score (CPS) ≥1 were analysed at baseline via cytofluorimetry for the expression of CD137, and it was found that the percentage of CD3⁺CD137⁺ cells is correlated with the clinical benefit rate (CBR), PFS, and OS. The results show that levels of circulating CD137⁺ T cells are significantly higher in responder patients than in non-responders (p = 0.03). Moreover, patients with CD3⁺CD137⁺ percentage ≥1.65% had prolonged OS (p = 0.02) and PFS (p = 0.02). Multivariate analysis, on a combination of biological and clinical parameters, showed that high levels of CD3⁺CD137⁺ cells (≥1.65%) and performance status (PS) = 0 are independent prognostic factors of PFS (CD137⁺ T cells, p = 0.007; PS, p = 0.002) and OS (CD137⁺ T cells, p = 0.006; PS, p = 0.001). Our results suggest that levels of circulating CD137⁺ T cells could serve as biomarkers for predicting the response of (R/M) HNSCC patients to pembrolizumab treatment, thus contributing to the success of anti-cancer treatment. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance)

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18 pages, 5955 KiB

Open AccessArticle

4-1BB-Based CAR T Cells Effectively Reverse Exhaustion and Enhance the Anti-Tumor Immune Response through Autocrine PD-L1 scFv Antibody

by Kang Cheng, Xiangming Feng, Zhirong Chai, Zhenzhen Wang, Zheng Liu, Zhanchao Yan, Yanming Wang and Shoutao Zhang

Int. J. Mol. Sci. 2023, 24(4), 4197; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24044197 - 20 Feb 2023

Cited by 3 | Viewed by 2636

Abstract

Exhaustion of chimeric antigen receptor (CAR) T cells is one of the limitations for CAR T efficacy in solid tumors and for tumor recurrence after initial CAR T treatment. Tumor treatment with a combination of programmed cell death receptor-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockage and CD28-based CAR T cells has been intensively studied. However, it remains largely unclear whether autocrine single-chain variable fragments (scFv) PD-L1 antibody can improve 4-1BB-based CAR T cell anti-tumor activity and revert CAR T cell exhaustion. Here, we studied T cells engineered with autocrine PD-L1 scFv and 4-1BB-containing CAR. The antitumor activity and exhaustion of CAR T cells were investigated in vitro and in a xenograft cancer model using NCG mice. CAR T cells with autocrine PD-L1 scFv antibody demonstrate enhanced anti-tumor activity in solid tumors and hematologic malignancies by blocking the PD-1/PD-L1 signaling. Importantly, we found that CAR T exhaustion was largely diminished by autocrine PD-L1 scFv antibody in vivo. As such, 4-1BB CAR T with autocrine PD-L1 scFv antibody combined the power of CAR T cells and the immune checkpoint inhibitor, thereby increasing the anti-tumor immune function and CAR T persistence, providing a cell therapy solution for a better clinical outcome. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance)

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17 pages, 21667 KiB

Open AccessArticle

A Novel Molecular Signature of Cancer-Associated Fibroblasts Predicts Prognosis and Immunotherapy Response in Pancreatic Cancer

by Weiyu Ge, Ming Yue, Yanling Wang, Yongchao Wang, Shengbai Xue, Daiyuan Shentu, Tiebo Mao, Xiaofei Zhang, Haiyan Xu, Shumin Li, Jingyu Ma, Liwei Wang and Jiujie Cui

Int. J. Mol. Sci. 2023, 24(1), 156; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010156 - 21 Dec 2022

Cited by 3 | Viewed by 1963

Abstract

Cancer-associated fibroblasts (CAFs), a prominent population of stromal cells, play a crucial role in tumor progression, prognosis, and treatment response. However, the relationship among CAF-based molecular signatures, clinical outcomes, and tumor microenvironment infiltration remains largely elusive in pancreatic cancer (PC). Here, we collected multicenter PC data and performed integrated analysis to investigate the role of CAF-related genes (CRGs) in PC. Firstly, we demonstrated that α-SMA⁺ CAFs were the most prominent stromal components and correlated with the poor survival rates of PC patients in our tissue microarrays. Then, we discriminated two diverse molecular subtypes (CAF clusters A and B) and revealed the significant differences in the tumor immune microenvironment (TME), four reported CAF subpopulations, clinical characteristics, and prognosis in PC samples. Furthermore, we analyzed their association with the immunotherapy response of PC patients. Lastly, a CRG score was constructed to predict prognosis, immunotherapy responses, and chemosensitivity in pancreatic cancer patients. In summary, these findings provide insights into further research targeting CAFs and their TME, and they pave a new road for the prognosis evaluation and individualized treatment of PC patients. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance)

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Review

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24 pages, 1158 KiB

Open AccessReview

The Bladder Tumor Microenvironment Components That Modulate the Tumor and Impact Therapy

by Mugdha Vijay Patwardhan and Ratha Mahendran

Int. J. Mol. Sci. 2023, 24(15), 12311; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241512311 - 01 Aug 2023

Cited by 2 | Viewed by 1870

Abstract

The tumor microenvironment (TME) is complex and involves many different cell types that seemingly work together in helping cancer cells evade immune monitoring and survive therapy. The advent of single-cell sequencing has greatly increased our knowledge of the cell types present in the tumor microenvironment and their role in the developing cancer. This, coupled with clinical data showing that cancer development and the response to therapy may be influenced by drugs that indirectly influence the tumor environment, highlights the need to better understand how the cells present in the TME work together. This review looks at the different cell types (cancer cells, cancer stem cells, endothelial cells, pericytes, adipose cells, cancer-associated fibroblasts, and neuronal cells) in the bladder tumor microenvironment. Their impact on immune activation and on shaping the microenvironment are discussed as well as the effects of hypertensive drugs and anesthetics on bladder cancer. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance)

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13 pages, 2812 KiB

Open AccessReview

Soluble PD-L1 as a Prognostic Factor for Immunotherapy Treatment in Solid Tumors: Systematic Review and Meta-Analysis

by Fabio Scirocchi, Lidia Strigari, Alessandra Di Filippo, Chiara Napoletano, Angelica Pace, Hassan Rahimi, Andrea Botticelli, Aurelia Rughetti, Marianna Nuti and Ilaria Grazia Zizzari

Int. J. Mol. Sci. 2022, 23(22), 14496; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214496 - 21 Nov 2022

Cited by 14 | Viewed by 2243

Abstract

Blocking the Programmed Cell Death Protein 1 (PD-1)/programmed death ligand-1 (PD-L1) axis has demonstrated great efficacy in cancer immunotherapy treatment and remains the central modality of immune targeting. To support the rational and tailored use of these drugs, it is important to identify reliable biomarkers related to survival. The role of the soluble form of the PD-L1 (sPD-L1) as a prognostic biomarker related to survival in solid cancer patients treated with immunotherapy has not yet been consistently evaluated. A systematic literature search of original articles in PubMed, MEDLINE and Scopus was conducted. Studies reporting hazard ratios (HRs) with a 95% confidence interval (CI) or Kaplan–Meier curves or individual patient data for overall survival (OS) or progression-free survival (PFS) associated with baseline levels of sPD-L1 in cancer patients undergoing immunotherapy treatment were considered eligible. Twelve studies involving 1076 patients and different tumor types treated with immunotherapy were included in the analysis. High blood levels of sPD-L1 correlated with poorer OS and PFS in cancer patients treated with immunotherapy (HR = 1.49, 95%CI: 1.15, 1.93, p < 0.01, I² = 77% for OS; HR = 1.59, 95%CI: 1.20, 2.12, p < 0.01, I² = 82% for PFS). A subgroup analysis highlighted that high levels of sPD-L1 were associated with worse survival in patients affected by NSCLC (HR = 1.81 95%CI: 1.09–3.00, p = 0.02, I² = 83% for OS; HR = 2.18, 95%CI: 1.27–3.76, p < 0.01, I² = 88% for PFS). An HR > 1 indicated that patients with low levels of sPD-L1 have the highest rates of OS/PFS. In this meta-analysis, we clarified the role of sPD-L1 in different solid cancers treated exclusively with Immune checkpoint inhibitors (ICIs). sPD-L1 could represent a non-invasive biomarker that is easily dosable in the blood of patients. The pooled data from the selected studies showed that a high circulating concentration of sPD-L1 in cancer patients correlates with worse survival, suggesting that it may be a helpful prognostic biomarker for the selection of cancer patients before immunotherapy, thus improving the efficacy of ICIs and avoiding unnecessary treatment. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance)

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18 pages, 1289 KiB

Open AccessReview

Interplay between the DNA Damage Response and Immunotherapy Response in Cancer

by Elizabeth Chun Yong Lee, Jessica Sook Ting Kok, Bin Tean Teh and Kah Suan Lim

Int. J. Mol. Sci. 2022, 23(21), 13356; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113356 - 01 Nov 2022

Cited by 4 | Viewed by 2495

Abstract

Genome instability and immune evasion are both defining hallmarks of cancer. Tumorigenesis is frequently initiated when there is DNA damage to a proto-oncogene or tumor suppressor gene and DNA repair mechanisms are lost or insufficient to correct the damage; immune evasion then prevents the host immune system from recognizing these transformed cells. Therapies targeting genomic instability and immune evasion have been effectively used to treat cancer. Genotoxic therapies such as chemoradiation have been employed in cancer treatments for several decades, while immunotherapy is a relatively new class of cancer therapy that has led to disease regression even in patients with advanced cancer. Several recent studies have shown synergy between both classes of therapy targeting these two defining hallmarks of cancer, and different mechanisms are proposed to be involved. Here, we review the different classes of DNA damage, their links to cancer, and their contribution to immunotherapy responses, as well as the different models that are currently being used to study tumor–immune interactions. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance)

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21 pages, 1360 KiB

Open AccessReview

The Multi-Dimensional Biomarker Landscape in Cancer Immunotherapy

by Jing Yi Lee, Bavani Kannan, Boon Yee Lim, Zhimei Li, Abner Herbert Lim, Jui Wan Loh, Tun Kiat Ko, Cedric Chuan-Young Ng and Jason Yongsheng Chan

Int. J. Mol. Sci. 2022, 23(14), 7839; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147839 - 16 Jul 2022

Cited by 14 | Viewed by 4447

Abstract

The field of immuno-oncology is now at the forefront of cancer care and is rapidly evolving. The immune checkpoint blockade has been demonstrated to restore antitumor responses in several cancer types. However, durable responses can be observed only in a subset of patients, highlighting the importance of investigating the tumor microenvironment (TME) and cellular heterogeneity to define the phenotypes that contribute to resistance as opposed to those that confer susceptibility to immune surveillance and immunotherapy. In this review, we summarize how some of the most widely used conventional technologies and biomarkers may be useful for the purpose of predicting immunotherapy outcomes in patients, and discuss their shortcomings. We also provide an overview of how emerging single-cell spatial omics may be applied to further advance our understanding of the interactions within the TME, and how these technologies help to deliver important new insights into biomarker discovery to improve the prediction of patient response. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance)

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14 pages, 322 KiB

Open AccessReview

CAR T Cell Therapy in Hematological Malignancies: Implications of the Tumor Microenvironment and Biomarkers on Efficacy and Toxicity

by Jing Yuan Tan, Muhammed Haiqal Low, Yunxin Chen and Francesca Lorraine Wei Inng Lim

Int. J. Mol. Sci. 2022, 23(13), 6931; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23136931 - 22 Jun 2022

Cited by 3 | Viewed by 2129

Abstract

Chimeric antigen receptor (CAR) T cell therapy has ushered in a new era in cancer treatment. Remarkable outcomes have been demonstrated in patients with previously untreatable relapsed/refractory hematological malignancies. However, optimizing efficacy and reducing the risk of toxicities have posed major challenges, limiting the success of this therapy. The tumor microenvironment (TME) plays an important role in CAR T cell therapy’s effectiveness and the risk of toxicities. Increasing research studies have also identified various biomarkers that can predict its effectiveness and risk of toxicities. In this review, we discuss the various aspects of the TME and biomarkers that have been implicated thus far and discuss the role of creating scoring systems that can aid in further refining clinical applications of CAR T cell therapy and establishing a safe and efficacious personalised medicine for individuals. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance)

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