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14 pages, 2868 KiB

Open AccessArticle

Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer

by Elie Marcheteau, Thomas Farge, Michaël Pérès, Guillaume Labrousse, Julie Tenet, Stéphanie Delmas, Maud Chusseau, Raphaëlle Duprez-Paumier, Camille Franchet, Florence Dalenc, Caroline Imbert, Justine Noujarède, Céline Colacios, Hervé Prats, Florence Cabon and Bruno Ségui

Cancers 2021, 13(16), 4059; https://doi.org/10.3390/cancers13164059 - 12 Aug 2021

Cited by 8 | Viewed by 4378

Abstract

Triple-negative breast cancer (TNBC) is notoriously aggressive with a high metastatic potential, and targeted therapies are lacking. Using transcriptomic and histologic analysis of TNBC samples, we found that a high expression of thrombospondin-1 (TSP1), a potent endogenous inhibitor of angiogenesis and an activator [...] Read more.

Triple-negative breast cancer (TNBC) is notoriously aggressive with a high metastatic potential, and targeted therapies are lacking. Using transcriptomic and histologic analysis of TNBC samples, we found that a high expression of thrombospondin-1 (TSP1), a potent endogenous inhibitor of angiogenesis and an activator of latent transforming growth factor beta (TGF-β), is associated with (i) gene signatures of epithelial–mesenchymal transition and TGF-β signaling, (ii) metastasis and (iii) a reduced survival in TNBC patients. In contrast, in tumors expressing low levels of TSP1, gene signatures of interferon gamma (IFN-γ) signaling and lymphocyte activation were enriched. In TNBC biopsies, TSP1 expression inversely correlated with the CD8+ tumor-infiltrating lymphocytes (TILs) content. In the 4T1 metastatic mouse model of TNBC, TSP1 silencing did not affect primary tumor development but, strikingly, impaired metastasis in immunocompetent but not in immunodeficient nude mice. Moreover, TSP1 knockdown increased tumor vascularization and T lymphocyte infiltration and decreased TGF-β activation in immunocompetent mice. Noteworthy was the finding that TSP1 knockdown increased CD8+ TILs and their programmed cell death 1 (PD-1) expression and sensitized 4T1 tumors to anti-PD-1 therapy. TSP1 inhibition might thus represent an innovative targeted approach to impair TGF-β activation and breast cancer cell metastasis and improve lymphocyte infiltration in tumors, and immunotherapy efficacy in TNBC. Full article

(This article belongs to the Special Issue Combination Therapy Strategies for Cancer PD-1/PD-L1 Pathway Blockade Awareness)

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17 pages, 2950 KiB

Open AccessArticle

Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients

by Kristine A. Frerichs, Christie P. M. Verkleij, Meletios A. Dimopoulos, Jhon A. Marin Soto, Sonja Zweegman, Mary H. Young, Kathryn J. Newhall, Tuna Mutis and Niels W. C. J. van de Donk

Cancers 2021, 13(10), 2452; https://doi.org/10.3390/cancers13102452 - 18 May 2021

Cited by 11 | Viewed by 3107

Abstract

Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 [...] Read more.

Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 blocking antibody durvalumab at the time of progression may reverse daratumumab-resistance. The efficacy and safety of daratumumab and durvalumab in daratumumab-refractory relapsed/refractory MM patients was evaluated in this prospective, single-arm phase 2 study (NCT03000452). None of the 18 enrolled patients achieved PR or better. The frequency of serious adverse events was 38.9%, with one patient experiencing an immune related adverse event (grade 2 hyperthyroidism). No infusion-related reactions were observed. Analysis of tumor- and immune cell characteristics was performed on bone marrow samples obtained at baseline and during treatment. Daratumumab combined with durvalumab reduced the frequency of regulatory T-cells and decreased the proportion of T-cells expressing LAG3 and CD8⁺ T-cells expressing TIM-3, without altering T- and NK-cell frequencies. Durvalumab did not affect tumor cell characteristics associated with daratumumab resistance. In conclusion, the addition of durvalumab to daratumumab following development of daratumumab-resistance was associated with an acceptable toxicity profile, but was not effective. This indicates that inhibition of the PD-1/PD-L1 signaling pathway at the time of daratumumab-resistance is insufficient to reverse daratumumab-resistance. Full article

(This article belongs to the Special Issue Combination Therapy Strategies for Cancer PD-1/PD-L1 Pathway Blockade Awareness)

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Review

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17 pages, 942 KiB

Open AccessReview

Combined Treatment with Immunotherapy-Based Strategies for MSS Metastatic Colorectal Cancer

by Iosune Baraibar, Oriol Mirallas, Nadia Saoudi, Javier Ros, Francesc Salvà, Josep Tabernero and Elena Élez

Cancers 2021, 13(24), 6311; https://doi.org/10.3390/cancers13246311 - 16 Dec 2021

Cited by 31 | Viewed by 5586

Abstract

In recent years, deepening knowledge of the complex interactions between the immune system and cancer cells has led to the advent of effective immunotherapies that have revolutionized the therapeutic paradigm of several cancer types. However, colorectal cancer (CRC) is one of the tumor [...] Read more.

In recent years, deepening knowledge of the complex interactions between the immune system and cancer cells has led to the advent of effective immunotherapies that have revolutionized the therapeutic paradigm of several cancer types. However, colorectal cancer (CRC) is one of the tumor types in which immunotherapy has proven less effective. While there is solid clinical evidence for the therapeutic role of immune checkpoint inhibitors in mismatch repair-deficient (dMMR) and in highly microsatellite instable (MSI-H) metastatic CRC (mCRC), blockade of CTLA-4 or PD-L1/PD-1 as monotherapy has not conferred any major clinical benefit to patients with MMR-proficient (pMMR) or microsatellite stable (MSS) mCRC, reflecting 95% of the CRC population. There thus remains a high unmet medical need for the development of novel immunotherapy approaches for the vast majority of patients with pMMR or MSS/MSI-low (MSI-L) mCRC. Defining the molecular mechanisms for immunogenicity in mCRC and mediating immune resistance in MSS mCRC is needed to develop predictive biomarkers and effective therapeutic combination strategies. Here we review available clinical data from combinatorial therapeutic approaches using immunotherapy-based strategies for MSS mCRC. Full article

(This article belongs to the Special Issue Combination Therapy Strategies for Cancer PD-1/PD-L1 Pathway Blockade Awareness)

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25 pages, 1238 KiB

Open AccessReview

Therapeutic Associations Comprising Anti-PD-1/PD-L1 in Breast Cancer: Clinical Challenges and Perspectives

by Fanny Ledys, Laura Kalfeist, Loick Galland, Emeric Limagne and Sylvain Ladoire

Cancers 2021, 13(23), 5999; https://doi.org/10.3390/cancers13235999 - 29 Nov 2021

Cited by 8 | Viewed by 2718

Abstract

Despite a few cases of long-responder patients, immunotherapy with anti-PD-(L)1 has so far proved rather disappointing in monotherapy in metastatic breast cancer, prompting the use of synergistic therapeutic combinations incorporating immunotherapy by immune-checkpoint inhibitors. In addition, a better understanding of both the mechanisms [...] Read more.

Despite a few cases of long-responder patients, immunotherapy with anti-PD-(L)1 has so far proved rather disappointing in monotherapy in metastatic breast cancer, prompting the use of synergistic therapeutic combinations incorporating immunotherapy by immune-checkpoint inhibitors. In addition, a better understanding of both the mechanisms of sensitivity and resistance to immunotherapy, as well as the immunological effects of the usual treatments for breast cancer, make it possible to rationally consider this type of therapeutic combination. For several years, certain treatments, commonly used to treat patients with breast cancer, have shown that in addition to their direct cytotoxic effects, they may have an impact on the tumor immune microenvironment, by increasing the antigenicity and/or immunogenicity of a “cold” tumor, targeting the immunosuppressive microenvironment or counteracting the immune-exclusion profile. This review focuses on preclinical immunologic synergic mechanisms of various standard therapeutic approaches with anti-PD-(L)1, and discusses the potential clinical use of anti-PD-1/L1 combinations in metastatic or early breast cancer. Full article

(This article belongs to the Special Issue Combination Therapy Strategies for Cancer PD-1/PD-L1 Pathway Blockade Awareness)

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17 pages, 953 KiB

Open AccessReview

Anti-PD-1/Anti-PD-L1 Drugs and Radiation Therapy: Combinations and Optimization Strategies

by Jihane Boustani, Benoît Lecoester, Jérémy Baude, Charlène Latour, Olivier Adotevi, Céline Mirjolet and Gilles Truc

Cancers 2021, 13(19), 4893; https://doi.org/10.3390/cancers13194893 - 29 Sep 2021

Cited by 18 | Viewed by 3462

Abstract

Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As [...] Read more.

Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials. Full article

(This article belongs to the Special Issue Combination Therapy Strategies for Cancer PD-1/PD-L1 Pathway Blockade Awareness)

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22 pages, 2384 KiB

Open AccessReview

Tumor-Derived Exosomes: Hidden Players in PD-1/PD-L1 Resistance

by Valentin Vautrot, Hafidha Bentayeb, Sébastien Causse, Carmen Garrido and Jessica Gobbo

Cancers 2021, 13(18), 4537; https://doi.org/10.3390/cancers13184537 - 10 Sep 2021

Cited by 22 | Viewed by 4660

Abstract

Recently, immunotherapy has garnered increasing importance in cancer therapy, leading to substantial improvements in patient care and survival. By blocking the immune checkpoints—protein regulators of the immune system—immunotherapy prevents immune tolerance toward tumors and reactivates the immune system, prompting it to fight cancer [...] Read more.

Recently, immunotherapy has garnered increasing importance in cancer therapy, leading to substantial improvements in patient care and survival. By blocking the immune checkpoints—protein regulators of the immune system—immunotherapy prevents immune tolerance toward tumors and reactivates the immune system, prompting it to fight cancer cell growth and diffusion. A widespread strategy for this is the blockade of the interaction between PD-L1 and PD-1. However, while patients generally respond well to immunotherapy, a certain proportion of patients present tumors that resist these treatments. This portion can be very high in some cancers and hinders cancer curability. For this reason, current efforts are focusing on combining PD-1/PD-L1 immunotherapy with the targeting of other immune checkpoints to counter resistance and achieve better results. Exosomes, small vesicles secreted by almost any cell, including tumor cells, have proven to be key actors in this resistance. The exosomes released by tumor cells spread the immune-suppressive properties of the tumor throughout the tumor microenvironment and participate in establishing metastatic niches. In this review, we will describe immune checkpoints and immune modulators whose presence in tumor-derived exosomes (TEXs) has been established. We will focus on the most promising proteins under scrutiny for use in combination with PD-1 blockade therapy in a clinical setting, such as PD-L1, CTLA-4, TIM-3, CD73/39, LAG-3, and TIGIT. We will explore the immunosuppressive impact of these exosomal proteins on a variety of immune cells. Finally, we will discuss how they can change the game in immunotherapy and guide therapeutic decisions, as well as the current limits of this approach. Depending on the viewpoint, these exosomal proteins may either provide key missing information on tumor growth and resistance mechanisms or they may be the next big challenge to overcome in improving cancer treatment. Full article

(This article belongs to the Special Issue Combination Therapy Strategies for Cancer PD-1/PD-L1 Pathway Blockade Awareness)

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25 pages, 9578 KiB

Open AccessReview

PD-1/PD-L1 Checkpoints and Resveratrol: A Controversial New Way for a Therapeutic Strategy

by Dominique Delmas, François Hermetet and Virginie Aires

Cancers 2021, 13(18), 4509; https://doi.org/10.3390/cancers13184509 - 7 Sep 2021

Cited by 11 | Viewed by 3671

Abstract

Immune checkpoints refer to a range of immunoregulatory molecules that modulate the immune response. For example, proteins expressed at the surface of T-cells (including PD-1 and CTLA-4) and their ligands (PD-L1 and B7-1/B7-2, respectively), expressed by cancer cells and antigen-presenting cells, are needed [...] Read more.

Immune checkpoints refer to a range of immunoregulatory molecules that modulate the immune response. For example, proteins expressed at the surface of T-cells (including PD-1 and CTLA-4) and their ligands (PD-L1 and B7-1/B7-2, respectively), expressed by cancer cells and antigen-presenting cells, are needed to prevent excessive immune responses. However, they dampen anti-tumor immunity by limiting T-cell activity, making them promising therapeutic targets in cancer. Although immunotherapies using checkpoint blocking/neutralizing antibodies targeting PD-L1 or PD-1 have proven their superiority over conventional chemotherapies or targeted therapies by enhancing T-cell-mediated anti-tumor immunity, some limitations have emerged. These include a relatively low rate of “responders” (<50%; irrespective of cancer type), the high cost of injections, and a rare risk of hyper-progression. For clinicians, the current challenge is thus to improve the existing therapies, potentially through combinatory approaches. Polyphenols such as resveratrol (RSV), a trihydroxystilbene found in various plants and an adjuvant in numerous nutraceuticals, have been proposed as potential therapeutic targets. Beyond its well-known pleiotropic effects, RSV affects PD-L1 and PD-1 expression as well as PD-L1 subcellular localization and post-translational modifications, which we review here. We also summarize the consequences of PD-1/PD-L1 signaling, the modalities of their blockade in the context of cancer, and the current status and limitations of these immunotherapies. Finally, we discuss their potential use in combination with chemotherapies, and, using RSV as a model, we propose polyphenols as adjuvants to enhance the efficacy of anti-PD-1/anti-PD-L1 immunotherapies. Full article

(This article belongs to the Special Issue Combination Therapy Strategies for Cancer PD-1/PD-L1 Pathway Blockade Awareness)

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19 pages, 1808 KiB

Open AccessReview

Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8⁺ T Cell Response in Hepatocellular Carcinoma

by Julia Peña-Asensio, Henar Calvo, Miguel Torralba, Joaquín Miquel, Eduardo Sanz-de-Villalobos and Juan-Ramón Larrubia

Cancers 2021, 13(8), 1922; https://doi.org/10.3390/cancers13081922 - 16 Apr 2021

Cited by 32 | Viewed by 4143

Abstract

Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens [...] Read more.

Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host’s antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8⁺ T cells is discussed in this review. Full article

(This article belongs to the Special Issue Combination Therapy Strategies for Cancer PD-1/PD-L1 Pathway Blockade Awareness)

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18 pages, 2902 KiB

Open AccessReview

Understanding Inflammasomes and PD-1/PD-L1 Crosstalk to Improve Cancer Treatment Efficiency

by Anaïs Perrichet, François Ghiringhelli and Cédric Rébé

Cancers 2020, 12(12), 3550; https://doi.org/10.3390/cancers12123550 - 27 Nov 2020

Cited by 12 | Viewed by 3045

Abstract

Inflammasomes and immune checkpoints have been shown to participate in carcinogenesis, cancer growth and response to treatment. Thus, targeting cytokines resulting from inflammasome activation, such as interleukin (IL)-1β, has emerged as a new tool in the therapeutic arsenal. Moreover, the use of checkpoint [...] Read more.

Inflammasomes and immune checkpoints have been shown to participate in carcinogenesis, cancer growth and response to treatment. Thus, targeting cytokines resulting from inflammasome activation, such as interleukin (IL)-1β, has emerged as a new tool in the therapeutic arsenal. Moreover, the use of checkpoint inhibitors such as anti-PD-1 or anti-PD-L1 has revolutionized the treatment of some cancer patients. However, inflammasome activation and consecutive cytokine release only occurs in some chemotherapeutic treatments and immune checkpoint inhibitors only work for a restricted number of patients, thus limiting the use of therapies targeting these pathways. Expanding knowledge about the inefficiency of these therapies recently brought forward the hypothesis of targeting both pathways. In this review, we provide an overview of the crosstalk between inflammasomes and programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) that might explain how these two pathways are mutually dependent, and perhaps why targeting only one of them leads to inefficiency of cancer treatment in some patients. Full article

(This article belongs to the Special Issue Combination Therapy Strategies for Cancer PD-1/PD-L1 Pathway Blockade Awareness)

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