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1.
Front Immunol ; 15: 1384121, 2024.
Article in English | MEDLINE | ID: mdl-38903504

ABSTRACT

The past decade has witnessed a revolution in cancer treatment, shifting from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based therapies, in particular immune-checkpoint inhibitors (ICIs). These immunotherapies release the host's immune system against the tumor and have shown unprecedented durable remission for patients with cancers that were thought incurable, such as metastatic melanoma, metastatic renal cell carcinoma (RCC), microsatellite instability (MSI) high colorectal cancer and late stages of non-small cell lung cancer (NSCLC). However, about 80% of the patients fail to respond to these immunotherapies and are therefore left with other less effective and potentially toxic treatments. Identifying and understanding the mechanisms that enable cancerous cells to adapt to and eventually overcome therapy can help circumvent resistance and improve treatment. In this review, we describe the recent discoveries on the onco-immunological processes which govern the tumor microenvironment and their impact on the resistance to PD-1/PD-L1 checkpoint blockade.


Subject(s)
Drug Resistance, Neoplasm , Immune Checkpoint Inhibitors , Neoplasms , Tumor Microenvironment , Humans , Immune Checkpoint Inhibitors/therapeutic use , Drug Resistance, Neoplasm/immunology , Tumor Microenvironment/immunology , Neoplasms/immunology , Neoplasms/drug therapy , Neoplasms/therapy , Animals , Immunotherapy/methods , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology
3.
Front Immunol ; 15: 1341079, 2024.
Article in English | MEDLINE | ID: mdl-38817612

ABSTRACT

Despite the efforts, pancreatic ductal adenocarcinoma (PDAC) is still highly lethal. Therapeutic challenges reside in late diagnosis and establishment of peculiar tumor microenvironment (TME) supporting tumor outgrowth. This stromal landscape is highly heterogeneous between patients and even in the same patient. The organization of functional sub-TME with different cellular compositions provides evolutive advantages and sustains therapeutic resistance. Tumor progressively establishes a TME that can suit its own needs, including proliferation, stemness and invasion. Cancer-associated fibroblasts and immune cells, the main non-neoplastic cellular TME components, follow soluble factors-mediated neoplastic instructions and synergize to promote chemoresistance and immune surveillance destruction. Unveiling heterotypic stromal-neoplastic interactions is thus pivotal to breaking this synergism and promoting the reprogramming of the TME toward an anti-tumor milieu, improving thus the efficacy of conventional and immune-based therapies. We underscore recent advances in the characterization of immune and fibroblast stromal components supporting or dampening pancreatic cancer progression, as well as novel multi-omic technologies improving the current knowledge of PDAC biology. Finally, we put into context how the clinic will translate the acquired knowledge to design new-generation clinical trials with the final aim of improving the outcome of PDAC patients.


Subject(s)
Carcinoma, Pancreatic Ductal , Drug Resistance, Neoplasm , Pancreatic Neoplasms , Tumor Microenvironment , Humans , Tumor Microenvironment/immunology , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/therapy , Drug Resistance, Neoplasm/immunology , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Animals , Cancer-Associated Fibroblasts/immunology , Cancer-Associated Fibroblasts/metabolism , Immune Tolerance
4.
Hum Cell ; 37(4): 931-943, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38814516

ABSTRACT

Immunosuppressive regulatory cells (IRCs) play important roles in negatively regulating immune response, and are mainly divided into myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Large numbers of preclinical and clinical studies have shown that inhibition or reduction of IRCs could effectively elevate antitumor immune responses. However, several studies also reported that excessive inhibition of IRCs function is one of the main reasons causing the side effects of cancer immunotherapy. Therefore, the reasonable regulation of IRCs is crucial for improving the safety and efficiency of cancer immunotherapy. In this review, we summarised the recent research advances in the cancer immunotherapy by regulating the proportion of IRCs, and discussed the roles of IRCs in regulating tumour immune evasion and drug resistance to immunotherapies. Furthermore, we also discussed how to balance the potential opportunities and challenges of using IRCs to improve the safety of cancer immunotherapies.


Subject(s)
Immunotherapy , Myeloid-Derived Suppressor Cells , Neoplasms , T-Lymphocytes, Regulatory , Humans , Neoplasms/therapy , Neoplasms/immunology , Immunotherapy/methods , T-Lymphocytes, Regulatory/immunology , Myeloid-Derived Suppressor Cells/immunology , Tumor Escape/immunology , Drug Resistance, Neoplasm/immunology , Animals , Immunosuppression Therapy
5.
Crit Rev Oncol Hematol ; 198: 104362, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38614267

ABSTRACT

In the tumor microenvironment (TME), myeloid cells play a pivotal role. Myeloid-derived immunosuppressive cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), are central components in shaping the immunosuppressive milieu of the tumor. Within the TME, a majority of TAMs assume an M2 phenotype, characterized by their pro-tumoral activity. These cells promote tumor cell growth, angiogenesis, invasion, and migration. In contrast, M1 macrophages, under appropriate activation conditions, exhibit cytotoxic capabilities against cancer cells. However, an excessive M1 response may lead to pro-tumoral inflammation. As a result, myeloid cells have emerged as crucial targets in cancer therapy. This review concentrates on gastrointestinal tumors, detailing methods for targeting macrophages to enhance tumor radiotherapy and immunotherapy sensitivity. We specifically delve into monocytes and tumor-associated macrophages' various functions, establishing an immunosuppressive microenvironment, promoting tumorigenic inflammation, and fostering neovascularization and stromal remodeling. Additionally, we examine combination therapeutic strategies.


Subject(s)
Drug Resistance, Neoplasm , Gastrointestinal Neoplasms , Tumor Microenvironment , Humans , Gastrointestinal Neoplasms/therapy , Gastrointestinal Neoplasms/immunology , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/pathology , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Drug Resistance, Neoplasm/immunology , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/drug effects , Animals , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/drug effects , Tumor-Associated Macrophages/metabolism , Myeloid Cells/immunology , Myeloid Cells/drug effects , Immunotherapy/methods , Cell- and Tissue-Based Therapy/methods
6.
J Reprod Immunol ; 163: 104241, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38492533

ABSTRACT

Epithelial ovarian cancer (OC) is the deadliest female reproductive cancer; an estimated 13,270 women will die from OC in 2023. Platinum-based chemotherapy resistance mechanisms contribute to poor OC 5-year survival rates. Peripheral inflammation is linked to various disease states and we previously identified unique peritoneal microbial features predictive of OC. We hypothesized that unique peripheral immune profiles and peritoneal microbial features may be predictive of disease-free interval (time to recurrence) and response to chemotherapy in participants with OC. We also investigated self-rated health (SRH) scores in the context of peripheral inflammation as a potential screening tool for OC. Blood and peritoneal fluid were collected from participants with OC or a benign adnexal mass (BPM). Lymphocyte populations were analyzed using Fluorescence Activated Cell Sorting, serum cytokine levels were analyzed using the Human Th17 Magnetic Bead Panel assay and peritoneal fluid microbial features were analyzed using Next Generation Sequencing (NGS). Participants completed a standardized questionnaire on self-rated physical and emotional health. Participants were classified into three chemotherapy response categories: platinum-refractory, platinum-resistant or platinum-sensitive. A significant positive correlation was found between elevated inflammatory status on the day of surgery and longer disease-free interval. SRH measures did not correlate with immune status in participants with OC or a BPM. We identified a correlation between peritoneal microbial features and chemotherapy response. We conclude that immune dysbiosis may be useful in predicting OC recurrence. The immune findings reported here set the framework for additional studies utilizing immune profiles to predict platinum-based chemotherapy responsiveness in OC.


Subject(s)
Dysbiosis , Humans , Female , Middle Aged , Dysbiosis/immunology , Adult , Carcinoma, Ovarian Epithelial/immunology , Carcinoma, Ovarian Epithelial/drug therapy , Aged , Ovarian Neoplasms/immunology , Ovarian Neoplasms/drug therapy , Drug Resistance, Neoplasm/immunology , Prognosis , Microbiota/immunology , Microbiota/drug effects , Cytokines/metabolism , Cytokines/blood , Ascitic Fluid/immunology , Ascitic Fluid/microbiology
7.
Leuk Lymphoma ; 65(6): 720-735, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38454535

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) may be cured with anti-CD20 based chemoimmunotherapy in the majority of cases, however, relapsed/refractory disease occurs in 30-40% patients, and despite significant recent therapeutic advances, continues to represent an unmet clinical need. Bispecific antibodies represent a novel class of therapy currently in development for relapsed/refractory B-cell lymphoma. This review discusses the background clinical need, mechanism of action, and clinical data including efficacy and toxicity for bispecific antibodies in DLBCL, focusing on the most advanced class in development; CD20 targeting T-cell engaging antibodies. Emerging possibilities for future use of bispecific antibodies is also discussed, including novel and cytotoxic combination regimens in relapsed and first-line settings.


Subject(s)
Antibodies, Bispecific , Lymphoma, Large B-Cell, Diffuse , Humans , Antibodies, Bispecific/therapeutic use , Antibodies, Bispecific/pharmacology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/immunology , Drug Resistance, Neoplasm/immunology , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/adverse effects , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/drug therapy , Treatment Outcome , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects
8.
Cancer Res ; 84(9): 1475-1490, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38319231

ABSTRACT

Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells, T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pretreatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of antitumor CD8+ T cells in posttreatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1-resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression whereas nonresponders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacologic inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the antitumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance. SIGNIFICANCE: Loss of induction of immunogenic cell death in response to T-DM1 leads to resistance that can be overcome by targeting TACC3, providing an attractive strategy to improve the efficacy of T-DM1.


Subject(s)
Ado-Trastuzumab Emtansine , Breast Neoplasms , Immunogenic Cell Death , Microtubule-Associated Proteins , Receptor, ErbB-2 , Humans , Female , Breast Neoplasms/immunology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/genetics , Immunogenic Cell Death/drug effects , Receptor, ErbB-2/metabolism , Ado-Trastuzumab Emtansine/pharmacology , Ado-Trastuzumab Emtansine/therapeutic use , Animals , Mice , Microtubule-Associated Proteins/metabolism , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/immunology , Xenograft Model Antitumor Assays , Cell Line, Tumor , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , Drug Resistance, Neoplasm/immunology , Drug Resistance, Neoplasm/drug effects , Antigens, Neoplasm/immunology , Antigens, Neoplasm/genetics , Trastuzumab/pharmacology , Trastuzumab/therapeutic use , CD8-Positive T-Lymphocytes/immunology
9.
Gynecol Oncol ; 185: 83-94, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38377762

ABSTRACT

OBJECTIVE: Advanced-stage high-grade serous ovarian cancer (HGSOC) remains a deadly gynecologic malignancy with high rates of disease recurrence and limited, effective therapeutic options for patients. There is a significant need to better stratify HGSOC patients into platinum refractory (PRF) vs. sensitive (PS) cohorts at baseline to improve therapeutic responses and survival outcomes for PRF HGSOC. METHODS: We performed NanoString for GeoMx Digital Spatial Profile (G-DSP) multiplex protein analysis on PRF and PS tissue microarrays (TMAs) to study the bidirectional communication of cancer cells with immune cells in the tumor microenvironment (TME) of HGSOC. We demonstrate robust stratification of PRF and PS tumors at baseline using multiplex spatial proteomic biomarkers with implications for tailoring subsequent therapy. RESULTS: PS patients had elevated apoptotic and anti-tumor immune profiles, while PRF patients had dual AKT1 and WNT signaling with immunosuppressive profiles. We found that dual activity of AKT1 and WNT signaling supported the exclusion of immune cells, specifically tumor infiltrating lymphocytes (TILs), from the TME in PRF tumors, and this was not observed in PS tumors. The exclusion of immune cells from the TME of PRF tumors corresponded to abnormal endothelial cell structure in tumors with dual AKT1 and WNT signaling activity. CONCLUSIONS: We believe our findings provide improved understanding of tumor-immune crosstalk in HGSOC TME highlighting the importance of the relationship between AKT and WNT pathways, immune cell function, and platinum response in HGSOC.


Subject(s)
Drug Resistance, Neoplasm , Ovarian Neoplasms , Proteomics , Proto-Oncogene Proteins c-akt , Tumor Microenvironment , Humans , Female , Tumor Microenvironment/immunology , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/drug therapy , Proto-Oncogene Proteins c-akt/metabolism , Proteomics/methods , Drug Resistance, Neoplasm/immunology , Middle Aged , Cystadenocarcinoma, Serous/immunology , Cystadenocarcinoma, Serous/pathology , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/metabolism , Wnt Signaling Pathway/immunology , Aged , Lymphocytes, Tumor-Infiltrating/immunology
10.
Adv Sci (Weinh) ; 11(13): e2307613, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38286668

ABSTRACT

Cetuximab resistance is a significant challenge in cancer treatment, requiring the development of novel therapeutic strategies. In this study, a series of multivalent rhamnose (Rha)-modified nanobody conjugates are synthesized and their antitumor activities and their potential to overcome cetuximab resistance are investigated. Structure-activity relationship studies reveal that the multivalent conjugate D5, bearing sixteen Rha haptens, elicits the most potent innate fragment crystallizable (Fc) effector immunity in vitro and exhibits an excellent in vivo pharmacokinetics by recruiting endogenous antibodies. Notably, it is found that the optimal conjugate D5 represents a novel entity capable of reversing cetuximab-resistance induced by serine protease (PRSS). Moreover, in a xenograft mouse model, conjugate D5 exhibits significantly improved antitumor efficacy compared to unmodified nanobodies and cetuximab. The findings suggest that Rha-Nanobody (Nb) conjugates hold promise as a novel therapeutic strategy for the treatment of cetuximab-resistant tumors by enhancing the innate Fc effector immunity and enhancing the recruitment of endogenous antibodies to promote cancer cell clearance by innate immune cells.


Subject(s)
Drug Resistance, Neoplasm , ErbB Receptors , Rhamnose , Single-Domain Antibodies , Animals , Humans , Mice , Antibodies, Monoclonal, Humanized/therapeutic use , Cell Line, Tumor , Cetuximab/pharmacology , Cetuximab/therapeutic use , ErbB Receptors/immunology , Immunity, Innate , Single-Domain Antibodies/pharmacology , Drug Resistance, Neoplasm/immunology
11.
Semin Cancer Biol ; 86(Pt 2): 69-80, 2022 11.
Article in English | MEDLINE | ID: mdl-36064086

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by high resistance and poor response to chemotherapy. In addition, the poorly immunogenic pancreatic tumors constitute an immunosuppressive tumor microenvironment (TME) that render immunotherapy-based approaches ineffective. Understanding the mechanisms of therapy resistance, identifying new targets, and developing effective strategies to overcome resistance can significantly impact the management of PDAC patients. Chemokines are small soluble factors that are significantly deregulated during PDAC pathogenesis, contributing to tumor growth, metastasis, immune cell trafficking, and therapy resistance. Thus far, different chemokine pathways have been explored as therapeutic targets in PDAC, with some promising results in recent clinical trials. Particularly, immunotherapies such as immune check point blockade therapies and CAR-T cell therapies have shown promising results when combined with chemokine targeted therapies. Considering the emerging pathological and clinical significance of chemokines in PDAC, we reviewed major chemokine-regulated pathways leading to therapy resistance and the ongoing endeavors to target chemokine signaling in PDAC. This review discusses the role of chemokines in regulating therapy resistance in PDAC and highlights the continuing efforts to target chemokine-regulated pathways to improve the efficacy of various treatment modalities.


Subject(s)
Carcinoma, Pancreatic Ductal , Chemokines , Drug Resistance, Neoplasm , Pancreatic Neoplasms , Humans , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Chemokines/genetics , Chemokines/immunology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , Pancreatic Neoplasms
12.
Cancer Discov ; 12(8): OF3, 2022 08 05.
Article in English | MEDLINE | ID: mdl-35748592

ABSTRACT

Patients with refractory or relapsed multiple myeloma usually develop resistance to the two approved BCMA-targeting chimeric antigen receptor (CAR) T cells. A preliminary study of a new CAR T-cell therapy that zeroes in on the GPRC5D protein on multiple myeloma cells suggests that this approach is safe and effective. All 10 patients treated with the GPRC5D-targeting cells showed responses.


Subject(s)
Drug Resistance, Neoplasm , Immunotherapy, Adoptive , Multiple Myeloma , Receptors, Chimeric Antigen , Receptors, G-Protein-Coupled , B-Cell Maturation Antigen/antagonists & inhibitors , B-Cell Maturation Antigen/immunology , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , Humans , Immunotherapy, Adoptive/methods , Multiple Myeloma/immunology , Multiple Myeloma/therapy , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/therapeutic use , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/immunology , Receptors, G-Protein-Coupled/therapeutic use
13.
J Pathol Clin Res ; 8(5): 458-469, 2022 09.
Article in English | MEDLINE | ID: mdl-35762092

ABSTRACT

Programmed cell death-1 (PD-1) and its ligand (PD-L1) are significant mediators of immune suppression in the tumor microenvironment. We focused on the immunological impact of PD-1/PD-L1 signaling during tumor progression in colorectal carcinoma (CRC) and its association with resistance to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal carcinoma (LAd-RC). Histopathological and immunohistochemical analyses of 100 CRC cases (including 34 RC) without NCRT and 109 NCRT-treated LAd-RC cases were performed. Membranous tumoral PD-L1 expression was identified in 9 of 100 (9%) CRC cases, including 1 of 34 (2.9%) RC cases, but PD-L1 immunopositivity was not associated with any clinicopathological factors, with the exception of deficient mismatch repair (dMMR) status. In contrast, stromal PD-L1+ immune cells, which frequently exhibited coexpression of PD-1 and CD8 markers, were significantly correlated with tumor vessel invasion, nuclear ß-catenin+ tumor budding cancer stem cell (CSC)-like features, and unfavorable prognosis. In the LAd-RC cases, stromal CD8+ (but not PD-L1+) immune cell infiltration in pretreatment-biopsied samples was significantly and positively associated with therapeutic efficacy. After NCRT, tumoral PD-L1 expression was observed in only 2 of 83 (2.4%) tumors, independent of dMMR status, whereas high stromal PD-L1+ and tumoral nuclear ß-catenin positivity were significantly linked to a poor response to NCRT and high tumor budding features. In addition, high stromal PD-L1 immunoreactivity was significantly associated with poorer overall survival. In conclusion, a combination of stromal PD-L1+ immune cells and nuclear ß-catenin+ tumor budding may contribute to tumor progression in CRC and resistance to NCRT in LAd-RC, through formation of niche-like lesions that exhibit immune resistance and CSC properties.


Subject(s)
B7-H1 Antigen , Drug Resistance, Neoplasm , Programmed Cell Death 1 Receptor , Radiation Tolerance , Rectal Neoplasms , beta Catenin , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , Cell Nucleus/genetics , Cell Nucleus/immunology , Chemoradiotherapy, Adjuvant , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Disease Progression , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/immunology , Humans , Neoadjuvant Therapy , Prognosis , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , Radiation Tolerance/genetics , Radiation Tolerance/immunology , Rectal Neoplasms/genetics , Rectal Neoplasms/immunology , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , beta Catenin/genetics , beta Catenin/immunology
14.
Front Immunol ; 13: 791975, 2022.
Article in English | MEDLINE | ID: mdl-35185887

ABSTRACT

Human leukocyte antigen (HLA)-G is a nonclassical MHC Class I molecule, which was initially reported as a mediator of immune tolerance when expressed in extravillous trophoblast cells at the maternal-fetal interface. HLA-G is the only known ligand of killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4), an atypical family molecule that is widely expressed on the surface of NK cells. Unlike other KIR receptors, KIR2DL4 contains both an arginine-tyrosine activation motif in its transmembrane region and an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail, suggesting that KIR2DL4 may function as an activating or inhibitory receptor. The immunosuppressive microenvironment exemplified by a rewired cytokine network and upregulated immune checkpoint proteins is a hallmark of advanced and therapy-refractory tumors. Accumulating evidence has shown that HLA-G is an immune checkpoint molecule with specific relevance in cancer immune escape, although the role of HLA-G/KIR2DL4 in antitumor immunity is still uncharacterized. Our previous study had shown that HLA-G was a pivotal mediator of breast cancer resistance to trastuzumab, and blockade of the HLA-G/KIR2DL4 interaction can resensitize breast cancer to trastuzumab treatment. In this review, we aim to summarize and discuss the role of HLA-G/KIR2DL4 in the immune microenvironment of breast cancer. A better understanding of HLA-G is beneficial to identifying novel biomarker(s) for breast cancer, which is important for precision diagnosis and prognostic assessment. In addition, it is also necessary to unravel the mechanisms underlying HLA-G/KIR2DL4 regulation of the immune microenvironment in breast cancer, hopefully providing a rationale for combined HLA-G and immune checkpoints targeting for the effective treatment of breast cancer.


Subject(s)
Breast Neoplasms/genetics , HLA-G Antigens/genetics , Receptors, KIR2DL4/genetics , Tumor Microenvironment/genetics , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , Female , HLA-G Antigens/immunology , Humans , Killer Cells, Natural/immunology , Receptors, KIR2DL4/immunology , Tumor Microenvironment/immunology
15.
BMC Cancer ; 22(1): 154, 2022 Feb 08.
Article in English | MEDLINE | ID: mdl-35135489

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors prolong the survival of non-small cell lung cancer (NSCLC) patients. Although it has been acknowledged that there is some correlation between the efficacy of anti-programmed cell death-1 (PD-1) antibody therapy and immunohistochemical analysis, this technique is not yet considered foolproof for predicting a favorable outcome of PD-1 antibody therapy. We aimed to predict the efficacy of nivolumab based on a comprehensive analysis of RNA expression at the gene level in advanced NSCLC. METHODS: This was a retrospective study on patients with NSCLC who were administered nivolumab at the Kansai Medical University Hospital. To identify genes associated with response to anti-PD-1 antibodies, we grouped patients into responders (complete and partial response) and non-responders (stable and progressive disease) to nivolumab therapy. Significant genes were then identified for these groups using Welch's t-test. RESULTS: Among 42 analyzed cases (20 adenocarcinomas and 22 squamous cell carcinomas), enhanced expression of MAGE-A4, BBC3, and OTOA genes was observed in responders with adenocarcinoma, and enhanced expression of DAB2, HLA-DPB,1 and CDH2 genes was observed in responders with squamous cell carcinoma. CONCLUSIONS: This study predicted the efficacy of nivolumab based on a comprehensive analysis of mRNA expression at the gene level in advanced NSCLC. We also revealed different gene expression patterns as predictors of the effectiveness of anti PD-1 antibody therapy in adenocarcinoma and squamous cell carcinoma.


Subject(s)
Adenocarcinoma/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Nivolumab/therapeutic use , Adaptor Proteins, Signal Transducing/immunology , Adenocarcinoma/immunology , Adult , Aged , Aged, 80 and over , Antigens, CD/immunology , Antigens, Neoplasm/immunology , Apoptosis Regulatory Proteins/immunology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , Cadherins/immunology , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Squamous Cell/immunology , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , Female , GPI-Linked Proteins/immunology , Gene Expression/drug effects , Gene Expression/immunology , HLA-DP beta-Chains/immunology , Humans , Lung Neoplasms/immunology , Male , Middle Aged , Neoplasm Proteins/immunology , Predictive Value of Tests , Programmed Cell Death 1 Receptor/drug effects , Programmed Cell Death 1 Receptor/immunology , Proto-Oncogene Proteins/immunology , RNA, Messenger/drug effects , RNA, Messenger/immunology , Retrospective Studies , Treatment Outcome
16.
Nat Commun ; 13(1): 182, 2022 01 10.
Article in English | MEDLINE | ID: mdl-35013322

ABSTRACT

Combining immune checkpoint therapy (ICT) and targeted therapy holds great promises for broad and long-lasting anti-cancer therapies. However, combining ICT with anti-PI3K inhibitors have been challenging because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we find that intermittent but not daily dosing of a PI3Kα/ß/δ inhibitor, BAY1082439, on Pten-null prostate cancer models could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNα/IFNγ pathway activation, ß2-microglubin expression and CXCL10/CCL5 secretion. With its preferential regulatory T cell inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells, most likely via tertiary lymphoid structures. Once primed, tumors remain T cell-inflamed, become responsive to anti-PD-1 therapy and have durable therapeutic effect. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn "cold" tumors into T cell-inflamed ones, paving the way for successful ICT.


Subject(s)
Antibodies, Neutralizing/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Class I Phosphatidylinositol 3-Kinases/genetics , Immune Checkpoint Inhibitors/pharmacology , PTEN Phosphohydrolase/genetics , Programmed Cell Death 1 Receptor/genetics , Prostatic Neoplasms, Castration-Resistant/drug therapy , Animals , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Cell Line, Tumor , Cell Movement/drug effects , Chemokine CCL5/genetics , Chemokine CCL5/immunology , Chemokine CXCL10/genetics , Chemokine CXCL10/immunology , Class I Phosphatidylinositol 3-Kinases/immunology , Disease Models, Animal , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , Gene Expression Regulation, Neoplastic , Humans , Interferon-alpha/genetics , Interferon-alpha/immunology , Interferon-gamma/genetics , Interferon-gamma/immunology , Male , Mice , Mice, Knockout , PTEN Phosphohydrolase/deficiency , PTEN Phosphohydrolase/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Prostate/drug effects , Prostate/metabolism , Prostate/pathology , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Signal Transduction , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , beta 2-Microglobulin/genetics , beta 2-Microglobulin/immunology
17.
J Invest Dermatol ; 142(2): 435-444, 2022 02.
Article in English | MEDLINE | ID: mdl-34352265

ABSTRACT

CD4 T cells play a key role in anticancer immunity. In this study, we investigate the clinical relevance of circulating CD4 T helper type 1 (Th1) response against telomerase (anti-TERT Th1 response) in patients with melanoma. The spontaneous anti-TERT Th1 response was detected in 54.5% (85/156) of patients with melanoma before treatment. The prevalence of this systemic response was inversely related to Breslow thickness >1 mm and American Joint Committee on Cancer stage ≥II (P = 0.001 and 0.032, respectively). In contrast to patients treated with targeted therapies, the anti-TERT Th1 immunity was associated with an objective response after immune checkpoint inhibitors treatment. Hence, 86% (18/21) of responder patients exhibited pre-existing anti-TERT Th1 versus 35% (6/19) in nonresponders (P = 0.001). This response was also associated with increased progression-free survival and overall survival in patients with melanoma treated with immune checkpoint inhibitors (P = 0.0008 and 0.012, respectively). Collectively, the presence of circulating anti-TERT Th1 response is inversely related to melanoma evolution and appears to be a predictive factor of response to immunotherapy. Our results highlight the interest in telomerase-specific CD4 Th1 response as a promising blood-based biomarker of immune checkpoint inhibitors therapy in melanoma.


Subject(s)
Immune Checkpoint Inhibitors/therapeutic use , Melanoma/immunology , Skin Neoplasms/immunology , Telomerase/immunology , Th1 Cells/immunology , Adult , Aged , Drug Resistance, Neoplasm/immunology , Female , Follow-Up Studies , Humans , Immune Checkpoint Inhibitors/pharmacology , Male , Melanoma/blood , Melanoma/drug therapy , Melanoma/mortality , Middle Aged , Neoplasm Staging , Progression-Free Survival , Prospective Studies , Skin Neoplasms/blood , Skin Neoplasms/drug therapy , Skin Neoplasms/mortality
18.
J Exp Med ; 219(1)2022 01 03.
Article in English | MEDLINE | ID: mdl-34807232

ABSTRACT

Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS "CD8+ TOXPHOS cells." We validated that higher levels of OXPHOS in tumor- and peripheral blood-derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients.


Subject(s)
CD8-Positive T-Lymphocytes/drug effects , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Melanoma/therapy , Oxidative Phosphorylation/drug effects , T-Lymphocyte Subsets/drug effects , Adult , Aged , Algorithms , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cells, Cultured , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , Female , Gene Expression Profiling/methods , Humans , Immune Checkpoint Inhibitors/immunology , Male , Melanoma/genetics , Melanoma/immunology , Middle Aged , Models, Genetic , Outcome Assessment, Health Care/methods , RNA-Seq/methods , Single-Cell Analysis/methods , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
19.
Bull Cancer ; 108(10S): S195-S204, 2021 Oct.
Article in French | MEDLINE | ID: mdl-34920803

ABSTRACT

Bispecific antibodies are novel approaches of immunotherapy engaging immune cells to destroy tumor cells. Their structure is variable and underlies their pharmacocinetic properties. These coumpounds are now being evaluated across multiple hematological malignancies. The anti-CD3/CD19 antibody blinatumomab is the first in class and have been approved for the treatment of patients with Ph-negative B-cell acute lymphoblastic leukemia. Other emerging applications are lymphoma, multiple myeloma and acute myeloid leukemia. The safety profile of bispecific antibodies is acceptable while limited by neurotoxicity and cytokine-release syndrome. The present review aims to depict the landscape of emerging bispecific antibodies currently in development for hematological malignancies.


Subject(s)
Antibodies, Bispecific/therapeutic use , Hematologic Neoplasms/therapy , Immunotherapy/methods , Antibodies, Bispecific/adverse effects , Antibodies, Bispecific/immunology , Antineoplastic Agents, Immunological/therapeutic use , Cytokine Release Syndrome/etiology , Drug Resistance, Neoplasm/immunology , Hematologic Neoplasms/immunology , Humans , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/therapy , Lymphoma/immunology , Lymphoma/therapy , Multiple Myeloma/immunology , Multiple Myeloma/therapy , Neoplasms/immunology , Neoplasms/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy
20.
Bull Cancer ; 108(10S): S205-S212, 2021 Oct.
Article in French | MEDLINE | ID: mdl-34920804

ABSTRACT

Immunotherapies have recently emerged as potential game changers in the treatment of multiple myeloma (MM). Those include monoclonal antibodies (targeting CD38 or CS1), bispecific antibodies (BsAb, mainly targeting BCMA, GPRC5D or FcRH5), antibody-drug conjugate (mainly targeting BCMA) and CAR-T cells (mainly targeting BCMA). BsAb have the capacity to bind two different antigens, one at the tumor cell surface and one on T cells (CD3), recreating the immune synapse. In this article, we discuss the main clinical data on BsAb in MM, as well as their different constructs and the potential mechanism of resistance.


Subject(s)
Antibodies, Bispecific/therapeutic use , Immunotherapy/methods , Multiple Myeloma/therapy , ADP-ribosyl Cyclase 1/immunology , Antibodies, Bispecific/immunology , Antigens, Neoplasm/immunology , Drug Resistance, Neoplasm/immunology , Humans , Multiple Myeloma/immunology , Receptors, Fc/immunology , Receptors, G-Protein-Coupled/immunology , Signaling Lymphocytic Activation Molecule Family/immunology , T-Lymphocytes/immunology
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