RESUMEN
Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.
Asunto(s)
Agotamiento de Células T , Microambiente Tumoral , Animales , Ratones , Linfocitos T CD8-positivos , Diferenciación Celular , Linfocitos T CD4-PositivosRESUMEN
T-cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T-cell exhaustion, such as programmed death 1, can reinvigorate tumor-specific T cells and activate antitumor immunity in various types of cancer. In this study, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to cancer immunotherapy. CD106 in tumor-specific T cells suppressed antitumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to programmed death 1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for cancer immunotherapy. Significance: CD106 is specifically expressed in tumor-specific exhausted CD8+ T cells and inhibits the TCR signaling pathway by reducing surface expression of the TCR/CD3 complex to suppress antitumor immunity.
Asunto(s)
Linfocitos T CD8-positivos , Receptores de Antígenos de Linfocitos T , Transducción de Señal , Microambiente Tumoral , Linfocitos T CD8-positivos/inmunología , Animales , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Ratones , Humanos , Microambiente Tumoral/inmunología , Transducción de Señal/inmunología , Ratones Endogámicos C57BL , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígenos CD/genética , Femenino , Neoplasias/inmunología , Neoplasias/patología , Terapia de Inmunosupresión , Tolerancia Inmunológica/inmunología , Línea Celular Tumoral , Inmunoterapia/métodosRESUMEN
Immune checkpoint inhibitors (ICIs) are indicated for a diverse range of cancer types, and characterizing the tumor immune microenvironment is critical for optimizing therapeutic strategies, including ICIs. T cell infiltration and activation status in the tumor microenvironment greatly affects the efficacy of ICIs. Here, we show that semaphorin 6D (Sema6D) forward signaling, which is reportedly involved in coordinating the orientation of cell development and migration as a guidance factor, impaired the infiltration and activation of tumor-specific CD8+ T cells in murine oral tumors. Sema6D expressed by nonhematopoietic cells was responsible for this phenotype. Plexin-A4, a receptor for Sema6D, inhibited T cell infiltration and partially suppressed CD8+ T cell activation and proliferation induced by Sema6D stimulation. Moreover, mouse oral tumors, which are resistant to PD-1-blocking treatment in wild-type mice, showed a response to the treatment in Sema6d-KO mice. Finally, analyses of public data sets of human head and neck squamous cell carcinoma, pan-cancer cohorts, and a retrospective cohort study showed that SEMA6D was mainly expressed by nonhematopoietic cells such as cancer cells, and SEMA6D expression was significantly negatively correlated with CD8A, PDCD1, IFNG, and GZMB expression. Thus, targeting Sema6D forward signaling is a promising option for increasing ICI efficacy.
Asunto(s)
Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Animales , Humanos , Ratones , Proliferación Celular , Neoplasias de Cabeza y Cuello/genética , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Microambiente TumoralRESUMEN
This study identified the anatomy of the vertical lingual muscle and functional relationships between the vertical lingual and the other lingual muscles in the human tongue. Three whole tongues were obtained from adult human cadavers and were used for histological study by the serial section method. At the tip of the tongue, the fibers of the vertical lingual muscle cross with the transverse lingual muscle, and extend inferiorly to the fibers of the inferior longitudinal lingual muscle. At the body of the tongue, the fibers of the vertical lingual muscle are located between the fibers of the superior longitudinal lingual and inferior longitudinal lingual muscle, crossing the fibers of the transverse lingual muscle, instead of crossing the fibers of the extrinsic lingual muscles. At the base of the tongue, the fibers of the vertical lingual muscle start by the fibers of the superior longitudinal lingual muscle, and connect with the fibers of the posterior muscle bundle of the styloglossus muscle. The average diameters of the vertical lingual muscle fibers increased gradually as they approached the base of the tongue. These findings suggest that posterosuperior movement of the tongue body may be accomplished with downward movement of the tip of the tongue by contractions of both the vertical lingual and the styloglossus muscle. The inferior longitudinal lingual muscle may also play a supporting role for the vertical lingual muscle at the tip of the tongue (AU)
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