RESUMO
Cancer immunotherapy has revolutionised cancer treatment, with immune checkpoint blockade (ICB) therapy and adoptive cell therapy (ACT) increasingly becoming standard of care across a growing number of cancer indications. While the majority of cancer immunotherapies focus on harnessing the anti-tumour CD8+ cytotoxic T cell response, the potential role of CD4+ 'helper' T cells has largely remained in the background. In this review, we give an overview of the multifaceted role of CD4+ T cells in the anti-tumour immune response, with an emphasis on recent evidence that CD4+ T cells play a bigger role than previously thought. We illustrate their direct anti-tumour potency and their role in directing a sustained immune response against tumours. We further highlight the emerging observation that CD4+ T cell responses against tumours tend to be against self-derived epitopes. These recent trends raise vital questions and considerations that will profoundly affect the rational design of immunotherapies to leverage on the full potential of the immune system against cancer.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Imunoterapia/métodos , Neoplasias/imunologia , Linfócitos T/imunologia , HumanosRESUMO
Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Proteína Relacionada a TNFR Induzida por Glucocorticoide/agonistas , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral/transplante , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/imunologia , Modelos Animais de Doenças , Feminino , Glioblastoma/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Memória Imunológica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise antitumor immune function. We discovered that inhibition of CARM1, an epigenetic enzyme and cotranscriptional activator, elicited beneficial antitumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their antitumor function and preserved memory-like populations required for sustained antitumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells, and natural killer cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of CARM1 with a small molecule elicited potent antitumor immunity and sensitized resistant tumors to checkpoint blockade. Targeting of this cotranscriptional regulator thus offers an opportunity to enhance immune function while simultaneously sensitizing resistant tumor cells to immune attack. SIGNIFICANCE: Resistance to cancer immunotherapy remains a major challenge. Targeting of CARM1 enables immunotherapy of resistant tumors by enhancing T-cell functionality and preserving memory-like T-cell populations within tumors. CARM1 inhibition also sensitizes resistant tumor cells to immune attack by inducing a tumor cell-intrinsic type 1 interferon response.This article is highlighted in the In This Issue feature, p. 1861.
Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/terapia , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Linhagem Celular Tumoral/efeitos dos fármacos , Humanos , Imunoterapia , Linfócitos T/efeitos dos fármacosRESUMO
Cytotoxic T cells play a key role in adaptive immunity by killing infected or cancerous cells. While the transcriptional control of CD8 T cell differentiation and effector function following T cell activation has been extensively studied, little is known about epigenetic regulation of these processes. Here we show that the histone deacetylase HDAC3 inhibits CD8 T cell cytotoxicity early during activation and is required for persistence of activated CD8 T cells following resolution of an acute infection. Mechanistically, HDAC3 inhibits gene programs associated with cytotoxicity and effector differentiation of CD8 T cells including genes encoding essential cytotoxicity proteins and key transcription factors. These data identify HDAC3 as an epigenetic regulator of the CD8 T cell cytotoxicity program.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Epigênese Genética , Histona Desacetilases/metabolismo , Linfócitos T Citotóxicos , Acetilação/efeitos dos fármacos , Acrilamidas/farmacologia , Animais , Antígenos/metabolismo , Sequência de Bases , Linfócitos T CD8-Positivos/efeitos dos fármacos , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/deficiência , Histonas/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Fenilenodiaminas/farmacologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Linfócitos T Citotóxicos/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacosRESUMO
A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain-derived class II-associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-Ag7 even in the absence of DM, and this property is related to the type 1 diabetes-associated ß57 polymorphism. We generated knock-in non-obese diabetic (NOD) mice with a single amino acid change in the CLIP segment of the invariant chain in order to moderately slow CLIP dissociation from I-Ag7 These knock-in mice had a significantly reduced incidence of spontaneous type 1 diabetes and diminished islet infiltration by CD4 T cells, in particular T cells specific for fusion peptides generated by covalent linkage of proteolytic fragments within ß cell secretory granules. Rapid CLIP dissociation enhanced the presentation of such extracellular peptides, thus bypassing the conventional MHC class II antigen-processing pathway. Autoimmunity-associated MHC class II polymorphisms therefore not only modify binding of self-peptides, but also alter the biochemistry of peptide acquisition.
Assuntos
Apresentação de Antígeno , Antígenos de Diferenciação de Linfócitos B/imunologia , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Linfócitos T CD4-Positivos/citologia , Técnicas de Introdução de Genes , Antígenos de Histocompatibilidade Classe II/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos TransgênicosRESUMO
MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.
Assuntos
Anticorpos Bloqueadores/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Melanoma/terapia , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Monoclonais/imunologia , Antígenos de Histocompatibilidade Classe I/química , Humanos , Imunocompetência , Ligantes , Melanoma/imunologia , Melanoma/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Metástase Neoplásica , Domínios Proteicos/imunologia , Receptores de IgG/imunologiaRESUMO
Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of >100 genes-including Pbrm1, Arid2, and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex-sensitized mouse B16F10 melanoma cells to killing by T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.