RESUMO
Immuno-oncology has gained momentum with the approval of antibodies with clinical activities in different indications. Unfortunately, for anti-PD (L)1 agents in monotherapy, only half of the treated population achieves a clinical response. For other agents, such as anti-CTLA4 antibodies, no biomarkers exist, and tolerability can limit administration. In this study, using publicly available genomic datasets, we evaluated the expression of the macrophage scavenger receptor-A (SR-A) (MSR1) and its association with a response to check-point inhibitors (CPI). MSR1 was associated with the presence of macrophages, dendritic cells (DCs) and neutrophils in most of the studied indications. The presence of MSR1 was associated with macrophages with a pro-tumoral phenotype and correlated with TIM3 expression. MSR1 predicted favorable overall survival in patients treated with anti-PD1 (HR: 0.56, FDR: 1%, p = 2.6 × 10-5), anti PD-L1 (HR: 0.66, FDR: 20%, p = 0.00098) and anti-CTLA4 (HR: 0.37, FDR: 1%, p = 4.8 × 10-5). When specifically studying skin cutaneous melanoma (SKCM), we observed similar effects for anti-PD1 (HR: 0.65, FDR: 50%, p = 0.0072) and anti-CTLA4 (HR: 0.35, FDR: 1%, p = 4.1 × 10-5). In a different dataset of SKCM patients, the expression of MSR1 predicted a clinical response to anti-CTLA4 (AUC: 0.61, p = 2.9 × 10-2). Here, we describe the expression of MSR1 in some solid tumors and its association with innate cells and M2 phenotype macrophages. Of note, the presence of MSR1 predicted a response to CPI and, particularly, anti-CTLA4 therapies in different cohorts of patients. Future studies should prospectively explore the association of MSR1 expression and the response to anti-CTLA4 strategies in solid tumors.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Perfilação da Expressão Gênica , Transcriptoma , Oncologia , Receptores Depuradores Classe ARESUMO
The identification of targets that are expressed on the cell membrane is a main goal in cancer research. The Lymphocyte Antigen 6 Family Member G6D (LY6G6D) gene codes for a protein that is mainly present on the surface of colorectal cancer (CRC) cells. Therapeutic strategies against this protein like the development of T cell engagers (TCE) are currently in the early clinical stage. In the present work, we interrogated public genomic datasets including TCGA to evaluate the genomic and immunologic cell profile present in tumors with high expression of LY6G6D. We used data from TCGA, among others, and the Tumor Immune Estimation Resource (TIMER2.0) platform for immune cell estimations and Spearman correlation tests. LY6G6D expression was exclusively present in CRC, particularly in the microsatellite stable (MSS) subtype, and was associated with left-side tumors and the canonical genomic subgroup. Tumors with mutations of APC and p53 expressed elevated levels of LY6G6D. This protein was expressed in tumors with an inert immune microenvironment with an absence of immune cells and co-inhibitory molecules. In conclusion, we described clinical, genomic and immune-pathologic characteristics that can be used to optimize the clinical development of agents against this target. Future studies should be performed to confirm these findings and potentially explore the suggested clinical development options.
Assuntos
Neoplasias Colorretais , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Feminino , Masculino , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Regulação Neoplásica da Expressão Gênica , Mutação , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/genética , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Antígenos Ly/metabolismo , Antígenos Ly/genética , Antígenos B7/genética , Antígenos B7/metabolismoRESUMO
The identification of surfaceome proteins is a main goal in cancer research to design antibody-based therapeutic strategies. T cell engagers based on KLK2, a kallikrein specifically expressed in prostate cancer (PRAD), are currently in early clinical development. Using genomic information from different sources, we evaluated the immune microenvironment and genomic profile of prostate tumors with high expression of KLK2. KLK2 was specifically expressed in PRAD but it was not significant associated with Gleason score. Additionally, KLK2 expression did not associate with the presence of any immune cell population and T cell activating markers. A mild correlation between the high expression of KLK2 and the deletion of TMPRSS2 was identified. KLK2 expression associated with high levels of surface proteins linked with a detrimental response to immune checkpoint inhibitors (ICIs) including CHRNA2, FAM174B, OR51E2, TSPAN1, PTPRN2, and the non-surface protein TRPM4. However, no association of these genes with an outcome in PRAD was observed. Finally, the expression of these genes in PRAD did not associate with an outcome in PRAD and any immune populations. We describe the immunologic microenvironment on PRAD tumors with a high expression of KLK2, including a gene signature linked with an inert immune microenvironment, that predicts the response to ICIs in other tumor types. Strategies targeting KLK2 with T cell engagers or antibody-drug conjugates will define whether T cell mobilization or antigen release and stimulation of immune cell death are sufficient effects to induce clinical activity.
Assuntos
Calicreínas , Neoplasias da Próstata , Receptores Odorantes , Humanos , Masculino , Genômica , Calicreínas/genética , Calicreínas/imunologia , Calicreínas/metabolismo , Proteínas de Neoplasias , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Tetraspaninas , Microambiente Tumoral/genéticaRESUMO
Therapeutic strategies targeting non-adaptive immune cells are currently in clinical development. γδT cells are a small subtype of T cells (1-10% of total T cells) that mediate their effector function without the necessity of the antigen presenting machinery, and also share functional properties with innate cells. Among the different γδT subtypes, antibodies against Vγ9Vδ2T have reported signs of clinical efficacy in early clinical studies. In this review we describe the biology of this subtype of non-conventional T cells and provide insights into the mechanism of action of novel antibodies that activate these cells. We will focus on antibodies targeting the BTN3A ligand and bi-specific γδT cell engagers. We will review in detail the advantages of these strategies including the potential for overcoming mechanisms of resistance to check point inhibitors, or the much more adequate safety profile compared with agents activating classical T cells. Limitations identified during the first studies in humans and strategies to overcome them will be revised and discussed. Finally, clinical options for future clinical development will be suggested.
Assuntos
Receptores de Antígenos de Linfócitos T gama-delta , Humanos , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Animais , Butirofilinas/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Imunoterapia/métodos , Linfócitos Intraepiteliais/imunologia , Antígenos CDRESUMO
Colorectal cancer (CRC) is the third most common cancer worldwide. Recent experiments suggest that CDK12 can be a good therapeutic target in CRC, and therefore, novel inhibitors targeting this protein are currently in preclinical development. Lipid-based formulations of chemical entities have demonstrated the ability to enhance activity while improving the safety profile. In the present work, we explore the antitumor activity of a new CDK12 inhibitor (CDK12-IN-E9, CDK12i) and its lipid-based formulation (LP-CDK12i) in CRC models, to increase efficacy. SW620, SW480 and HCT116 CRC cell lines were used to evaluate the inhibitor and the liposomal formulation using MTT proliferation assay, 3D invasion cultures, flow cytometry, Western blotting and immunofluorescence experiments. Free-cholesterol liposomal formulations of CDK12i (LP-CDK12i) were obtained by solvent injection method and fully characterized by size, shape, polydispersity, encapsulation efficiency, and release profile and stability assessments. LP-CDK12i induced a higher antiproliferative effect compared with CDK12i as a free agent. The IC50 value was lower across all cell lines tested, leading to a reduction in cell proliferation and the formation of 3D structures. Evaluation of apoptosis revealed an increase in cell death, while biochemical studies demonstrated modifications of apoptosis and DNA damage components. In conclusion, we confirm the role of targeting CDK12 for the treatment of CRC and describe, for the first time, a liposomal formulation of a CDK12i with higher antiproliferative activity compared with the free compound.
RESUMO
BACKGROUND: The identification of proteins in the cellular membrane of the tumoral cell is a key to the design of therapeutic agents. Recently, the bi-specific antibody amivantamab, targeting the oncogenic membrane proteins EGFR and MET, received regulatory approval for the treatment of adult patients with locally advanced or metastatic NSCLC. METHODS: The authors interrogated several publicly available genomic datasets to evaluate the expression of both receptors and PD-L1 in most of the solid and hematologic malignancies and focused on prostate adenocarcinoma (PRAD) and pancreatic adenocarcinoma (PAAD). RESULTS: In PAAD, EGFR highly correlated with PD-L1 and MET, and MET showed a moderate correlation with PD-L1, while in PRAD, EGFR, MET and PD-L1 showed a strong correlation. In addition, in tumors treated with immune checkpoint inhibitors, including anti-PD(L)1 and anti-CTLA4, a high expression of EGFR and MET predicted detrimental survival. When exploring the relationship of immune populations with these receptors, the authors observed that in PAAD and PRAD, EGFR moderately correlated with CD8+ T cells. Furthermore, EGFR and MET correlated with neutrophils in PRAD. CONCLUSIONS: The authors identified tumor types where EGFR and MET were highly expressed and correlated with a high expression of PD-L1, opening the door for the future combination of bi-specific EGFR/MET antibodies with anti-PD(L)1 inhibitors.
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INTRODUCTION: Antibody-drug conjugates (ADCs) are a family of therapeutic agents that have demonstrated clinical activity in several indications. MATERIAL AND METHODS: In this article, we performed a deep analysis of their clinical landscape matched with public genomic human datasets from tumour antigen targets (TATs), to identify empty areas for clinical development. RESULTS: We observed that TATs used in haematological malignancies were more specific than the ones developed in solid cancers. Those included CD19, CD22, CD30, CD33 and CD79b. In solid tumours, we identified TATs, with approved ADCs, widely expressed in non-explored niche indications like Enfortumab vedotin (anti-Nectin4) in lung or cervical cancer; Tisotumab vedotin (anti-TF) in glioblastoma or pancreatic cancer; and Sacituzumab govitecan (anti-TROP2) in pancreatic, gastric, thyroid or endometrial cancer, among others. Similarly, niche indications for ADCs in clinical development included targets for CD71, PSMA, PTK7 or CD74, in tumours like breast, lung, stomach or colon. Some of these TATs were essential for the survival of tumour cells like CD71, PSMA and PTK7. CONCLUSIONS: In summary, our study opens the door for further evaluation of ADCs in several indications not explored before.
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Antibody-drug conjugates (ADCs) have emerged as a novel therapeutic strategy that has successfully reached patient treatment in different clinical scenarios. ADCs are formed by an antibody against a specific tumor-associated antigen (TAA), a cytotoxic payload, and a chemical linker that binds both. To this regard, most efforts have been focused on target identification, antibody design and linker optimization, but other relevant aspects for clinical development have not received the necessary attention. In this article using data from approved ADCs, we evaluated all characteristics of these agents, including payload physicochemical properties, in vitro potency, drug antibody ratio (DAR), exposure-response relationships, and clinical development strategies. We suggest that compounds with best options for clinical development include those with optimal payload physicochemical properties and cleavable linkers that would lead to a bystander effect. These modalities can facilitate the development of ADCs in indications with low expression of the TAA. Early clinical development strategies including changes in the schedule of administration with more frequent doses are also discussed in the context of an efficient strategy. In conclusion, we highlight relevant aspects that are needed for the optimal development of ADCs in cancer, proposing options for improvement.
Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Imunoconjugados/uso terapêutico , Imunoconjugados/química , Anticorpos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Neoplasias/tratamento farmacológicoRESUMO
Identification of genomic alterations that influence the immune response within the tumor microenvironment is mandatory in order to identify druggable vulnerabilities. In this article, by interrogating public genomic datasets we describe copy number variations (CNV) present in breast cancer (BC) tumors and corresponding subtypes, associated with different immune populations. We identified regulatory T-cells associated with the Basal-like subtype, and type 2 T-helper cells with HER2 positive and the luminal subtype. Using gene set enrichment analysis (GSEA) for the Type 2 T-helper cells, the most relevant processes included the ERBB2 signaling pathway and the Fibroblast Growth Factor Receptor (FGFR) signaling pathway, and for CD8+ T-cells, cellular response to growth hormone stimulus or the JAK-STAT signaling pathway. Amplification of ERBB2, GRB2, GRB7, and FGF receptor genes strongly correlated with the presence of type 2 T helper cells. Finally, only 8 genes were highly upregulated and present in the cellular membrane: MILR1, ACE, DCSTAMP, SLAMF8, CD160, IL2RA, ICAM2, and SLAMF6. In summary, we described immune populations associated with genomic alterations with different BC subtypes. We observed a clear presence of inhibitory cells, like Tregs or Th2 when specific chromosomic regions were amplified in basal-like or HER2 and luminal groups. Our data support further evaluation of specific therapeutic strategies in specific BC subtypes, like those targeting Tregs in the basal-like subtype.