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Immune Responses in Cancer Immunology and Immunotherapy

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 40058

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Special Issue Editor

Dr. Alvaro Teijeira

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Guest Editor

Program for Immunology and Immunotherapy Department, CIMA, Universidad de Navarra, Pamplona, Spain
Interests: tumor immunology; intravital microscopy; cell migration

Special Issue Information

Dear Colleagues,

Cancer Immunotherapy has revolutionize the treatment of cancer thanks to the great success of immune checkpoint blockade and CAR T cells in several malignancies as Lung Cancer, Melanoma and some Leukemias and Lymphomas: Yet, additional immune escape mechanisms are deployed by cancer cells to inhibit immune responses, which in turn results in an important fraction of patients that cannot benefit from current immunotherapeutic approaches. Both poor tumor immunogenicity and the absence of an adequate immune cell infiltrate represent major challenges to overcome in cancer immunotherapy. Although a major effort has been made in understanding the mechanisms governing adaptive immune responses against cancer, thanks to the central role of T cells in mediating cancer rejection, growing evidence identifies Myeloid cells as key shapers of anti-cancer immunity by orchestrating processes as antigen presentation, inflammation or T cell suppression. This special issue will focus in translational research as the best tool to identify the mechanisms operating antitumor immunity in human cancer.

Dr. Alvaro Teijeira
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 Immunology
Immunotherapy
Tumor associated neutrophils
Myeloid derived suppressor cells
Dendritic cells
NK cells
Immune infiltration
Immune cell metabolism
Antigen Presentation
Neoantigens
Macrophages

Published Papers (11 papers)

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Research

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12 pages, 2083 KiB

Open AccessArticle

Identification of Tumor Antigens in Ovarian Cancers Using Local and Circulating Tumor-Specific Antibodies

by Jessica Da Gama Duarte, Luke T. Quigley, Anna Rachel Young, Masaru Hayashi, Mariko Miyazawa, Alex Lopata, Nunzio Mancuso, Mikio Mikami, Andreas Behren and Els Meeusen

Int. J. Mol. Sci. 2021, 22(20), 11220; https://doi.org/10.3390/ijms222011220 - 18 Oct 2021

Cited by 2 | Viewed by 2562

Abstract

Ovarian cancers include several disease subtypes and patients often present with advanced metastatic disease and a poor prognosis. New biomarkers for early diagnosis and targeted therapy are, therefore, urgently required. This study uses antibodies produced locally in tumor-draining lymph nodes (ASC probes) of individual ovarian cancer patients to screen two separate protein microarray platforms and identify cognate tumor antigens. The resulting antigen profiles were unique for each individual cancer patient and were used to generate a 50-antigen custom microarray. Serum from a separate cohort of ovarian cancer patients encompassing four disease subtypes was screened on the custom array and we identified 28.8% of all ovarian cancers, with a higher sensitivity for mucinous (50.0%) and serous (40.0%) subtypes. Combining local and circulating antibodies with high-density protein microarrays can identify novel, patient-specific tumor-associated antigens that may have diagnostic, prognostic or therapeutic uses in ovarian cancer. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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15 pages, 2483 KiB

Open AccessArticle

Inhibition of WHSC1 Allows for Reprogramming of the Immune Compartment in Prostate Cancer

by Muzamil Y. Want, Ellen Karasik, Bryan Gillard, A. J. Robert McGray and Sebastiano Battaglia

Int. J. Mol. Sci. 2021, 22(16), 8742; https://doi.org/10.3390/ijms22168742 - 14 Aug 2021

Cited by 6 | Viewed by 2375

Abstract

Immunotherapy initially demonstrated promising results in prostate cancer (PCa), but the modest or negative results of many recent trials highlight the need to overcome the poor immunogenicity of this cancer. The design of effective therapies for PCa is challenged by the limited understanding of the interface between PCa cells and the immune system in mediating therapeutic resistance. Prompted by our recent observations that elevated WHSC1, a histone methyltransferase known to promote progression of numerous cancers, can silence antigen processing and presentation in PCa, we performed a single-cell analysis of the intratumoral immune dynamics following in vivo pharmacological inhibition of WHSC1 in mice grafted with TRAMP C2 cells. We observed an increase in cytotoxic T and NK cells accumulation and effector function, accompanied by a parallel remodeling of the myeloid compartment, as well as abundant shifts in key ligand–receptor signaling pathways highlighting changes in cell-to-cell communication driven by WHSC1 inhibition. This comprehensive profiling of both immune and molecular changes during the course of WHSC1 blockade deepens our fundamental understanding of how anti-tumor immune responses develop and can be enhanced therapeutically for PCa. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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11 pages, 2922 KiB

Open AccessArticle

Prognostic and Therapeutic Implications of Immune Classification by CD8⁺ Tumor-Infiltrating Lymphocytes and PD-L1 Expression in Sinonasal Squamous Cell Carcinoma

by Rocío García-Marín, Sara Reda, Cristina Riobello, Virginia N. Cabal, Laura Suárez-Fernández, Blanca Vivanco, César Álvarez-Marcos, Fernando López, José L. Llorente and Mario A. Hermsen

Int. J. Mol. Sci. 2021, 22(13), 6926; https://doi.org/10.3390/ijms22136926 - 28 Jun 2021

Cited by 12 | Viewed by 2646

Abstract

Sinonasal squamous cell carcinoma (SNSCC) is an aggressive tumor predominantly arising in the maxillary sinus and nasal cavities. Advances in imaging, surgical and radiotherapeutic techniques have reduced complications and morbidity; however, the prognosis generally remains poor, with an overall 5-year survival rate of 30–50%. As immunotherapy may be a new therapeutic option, we analyzed CD8⁺ tumor-infiltrating lymphocytes (TILs) and the tumor microenvironment immune type (TMIT, combining CD8⁺ TILs and PD-L1) in a series of 57 SNSCCs. Using immunohistochemistry, tissue samples of 57 SNSCCs were analyzed for expression of CD8 on TILs and of PD-L1 on tumor cells. The results were correlated to the clinical and survival data. In total, 88% (50/57) of the tumors had intratumoral CD8⁺ TILs; 19% (11/57)—CD8^high (>10%); and 39/57 (68%)—CD8^low (1–10%). PD-L1 positivity (>5%) was observed in 46% (26/57) of the SNSCCs and significantly co-occurred with CD8⁺ TILs (p = 0.000). Using univariate analysis, high intratumoral CD8⁺ TILs and TMIT I (CD8^high/PD-L1^pos) correlated with a worse survival rate. These results indicate that SNSCCs are immunogenic tumors, similar to head and neck squamous cell carcinomas. Nineteen percent of the cases were both CD8^high and PD-L1^pos and this subgroup may benefit from therapy with immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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19 pages, 3491 KiB

Open AccessArticle

Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

by Chi Yan, Jinming Yang, Nabil Saleh, Sheau-Chiann Chen, Gregory D. Ayers, Vandana G. Abramson, Ingrid A. Mayer and Ann Richmond

Int. J. Mol. Sci. 2021, 22(10), 5207; https://doi.org/10.3390/ijms22105207 - 14 May 2021

Cited by 23 | Viewed by 3514

Abstract

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8⁺ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8⁺ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8⁺ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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Review

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12 pages, 1611 KiB

Open AccessReview

Ionic Regulation of T-Cell Function and Anti-Tumour Immunity

by Pierpaolo Ginefra, Helen Carrasco Hope, Mattia Spagna, Alessandra Zecchillo and Nicola Vannini

Int. J. Mol. Sci. 2021, 22(24), 13668; https://doi.org/10.3390/ijms222413668 - 20 Dec 2021

Cited by 5 | Viewed by 3318

Abstract

The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME). In the TME, T cells compete with cancer cells for macronutrients (sugar, proteins, and lipid) and micronutrients (vitamins and minerals/ions). While the role of macronutrients in T-cell activation and function is well characterized, the contribution of micronutrients and especially ions in anti-tumour T-cell activities is still under investigation. Notably, ions are important for most of the signalling pathways regulating T-cell anti-tumour function. In this review, we discuss the role of six biologically relevant ions in T-cell function and in anti-tumour immunity, elucidating potential strategies to adopt to improve immunotherapy via modulation of ion metabolism. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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16 pages, 2324 KiB

Open AccessReview

Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond

by Thomas Jung, Maximilian Haist, Michael Kuske, Stephan Grabbe and Matthias Bros

Int. J. Mol. Sci. 2021, 22(18), 9890; https://doi.org/10.3390/ijms22189890 - 13 Sep 2021

Cited by 15 | Viewed by 3536

Abstract

The advent of mitogen-activated protein kinase (MAPK) inhibitors that directly inhibit tumor growth and of immune checkpoint inhibitors (ICI) that boost effector T cell responses have strongly improved the treatment of metastatic melanoma. In about half of all melanoma patients, tumor growth is driven by gain-of-function mutations of BRAF (v-rat fibrosarcoma (Raf) murine sarcoma viral oncogene homolog B), which results in constitutive ERK activation. Patients with a BRAF mutation are regularly treated with a combination of BRAF and MEK (MAPK/ERK kinase) inhibitors. Next to the antiproliferative effects of BRAF/MEKi, accumulating preclinical evidence suggests that BRAF/MEKi exert immunomodulatory functions such as paradoxical ERK activation as well as additional effects in non-tumor cells. In this review, we present the current knowledge on the immunomodulatory functions of BRAF/MEKi as well as the non-intended effects of ICI and discuss the potential synergistic effects of ICI and MAPK inhibitors in melanoma treatment. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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14 pages, 660 KiB

Open AccessReview

Tying Small Changes to Large Outcomes: The Cautious Promise in Incorporating the Microbiome into Immunotherapy

by Justin Chau and Jun Zhang

Int. J. Mol. Sci. 2021, 22(15), 7900; https://doi.org/10.3390/ijms22157900 - 23 Jul 2021

Cited by 3 | Viewed by 2128

Abstract

The role of the microbiome in immunology is a rapidly burgeoning topic of study. Given the increasing use of immune checkpoint inhibitor (ICI) therapy in cancers, along with the recognition that carcinogenesis has been linked to dysregulations of the immune system, much attention is now directed at potentiation of ICI efficacy, as well as minimizing the incidence of treatment-associated immune-related adverse events (irAEs). We provide an overview of the major research establishing links between the microbiome to tumorigenesis, chemotherapy and radiation potentiation, and ICI efficacy and irAE development. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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38 pages, 3283 KiB

Open AccessReview

MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

by Elena Shklovskaya and Helen Rizos

Int. J. Mol. Sci. 2021, 22(13), 6741; https://doi.org/10.3390/ijms22136741 - 23 Jun 2021

Cited by 26 | Viewed by 6916

Abstract

It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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13 pages, 561 KiB

Open AccessReview

4-1BBL as a Mediator of Cross-Talk between Innate, Adaptive, and Regulatory Immunity against Cancer

by Alejandra G. Martinez-Perez, Jose J. Perez-Trujillo, Rodolfo Garza-Morales, Maria J. Loera-Arias, Odila Saucedo-Cardenas, Aracely Garcia-Garcia, Humberto Rodriguez-Rocha and Roberto Montes-de-Oca-Luna

Int. J. Mol. Sci. 2021, 22(12), 6210; https://doi.org/10.3390/ijms22126210 - 9 Jun 2021

Cited by 16 | Viewed by 6026

Abstract

The ability of tumor cells to evade the immune system is one of the main challenges we confront in the fight against cancer. Multiple strategies have been developed to counteract this situation, including the use of immunostimulant molecules that play a key role in the anti-tumor immune response. Such a response needs to be tumor-specific to cause as little damage as possible to healthy cells and also to track and eliminate disseminated tumor cells. Therefore, the combination of immunostimulant molecules and tumor-associated antigens has been implemented as an anti-tumor therapy strategy to eliminate the main obstacles confronted in conventional therapies. The immunostimulant 4-1BBL belongs to the tumor necrosis factor (TNF) family and it has been widely reported as the most effective member for activating lymphocytes. Hence, we will review the molecular, pre-clinical, and clinical applications in conjunction with tumor-associated antigens in antitumor immunotherapy, as well as the main molecular pathways involved in this association. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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16 pages, 545 KiB

Open AccessReview

Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

by Vicenç Ruiz de Porras, Juan Carlos Pardo, Lucia Notario, Olatz Etxaniz and Albert Font

Int. J. Mol. Sci. 2021, 22(9), 4712; https://doi.org/10.3390/ijms22094712 - 29 Apr 2021

Cited by 14 | Viewed by 3044

Abstract

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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11 pages, 607 KiB

Open AccessReview

Hyperprogressive Disease: Main Features and Key Controversies

by Hugo Arasanz, Miren Zuazo, Ana Bocanegra, Luisa Chocarro, Ester Blanco, Maite Martínez, Idoia Morilla, Gonzalo Fernández, Lucía Teijeira, Pilar Morente, Miriam Echaide, Natalia Castro, Leticia Fernández, Maider Garnica, Pablo Ramos, David Escors, Grazyna Kochan and Ruth Vera

Int. J. Mol. Sci. 2021, 22(7), 3736; https://doi.org/10.3390/ijms22073736 - 3 Apr 2021

Cited by 17 | Viewed by 2839

Abstract

Along with the positioning of immunotherapy as a preferential treatment for a wide variety of neoplasms, a new pattern of response consisting in a sudden acceleration of tumor growth has been described. This phenomenon has received the name of “hyperprogressive disease”, and several definitions have been proposed for its identification, most of them relying on radiological criteria. However, due to the fact that the cellular and molecular mechanisms have not been elucidated yet, there is still some debate regarding whether this fast progression is induced by immunotherapy or only reflects the natural course of some highly aggressive neoplasms. Moreover, contradictory results of trials including patients with different cancer types suggest that both the incidence, the associated factors and the implications regarding prognosis might differ depending on tumor histology. This article intends to review the main publications regarding this matter and critically approach the most controversial aspects. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

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