RESUMEN
Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies.
Asunto(s)
Células Dendríticas/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias/inmunología , Neoplasias/terapia , Óxido Nítrico Sintasa de Tipo II/inmunología , Linfocitos T Citotóxicos/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Arginasa/biosíntesis , Arginasa/inmunología , Antígenos CD40/inmunología , Ligando de CD40/inmunología , Línea Celular Tumoral , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Microambiente Tumoral , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Microsatellite instability in colorectal cancer predicts favorable outcomes. However, the mechanistic relationship between microsatellite instability, tumor-infiltrating immune cells, Immunoscore, and their impact on patient survival remains to be elucidated. We found significant differences in mutational patterns, chromosomal instability, and gene expression that correlated with patient microsatellite instability status. A prominent immune gene expression was observed in microsatellite-instable (MSI) tumors, as well as in a subgroup of microsatellite-stable (MSS) tumors. MSI tumors had increased frameshift mutations, showed genetic evidence of immunoediting, had higher densities of Th1, effector-memory T cells, in situ proliferating T cells, and inhibitory PD1-PDL1 cells, had high Immunoscores, and were infiltrated with mutation-specific cytotoxic T cells. Multivariate analysis revealed that Immunoscore was superior to microsatellite instability in predicting patients' disease-specific recurrence and survival. These findings indicate that assessment of the immune status via Immunoscore provides a potent indicator of tumor recurrence beyond microsatellite-instability staging that could be an important guide for immunotherapy strategies.
Asunto(s)
Neoplasias Colorrectales/diagnóstico , Inmunoensayo/métodos , Patología Molecular/métodos , Subgrupos de Linfocitos T/inmunología , Células TH1/inmunología , Anciano , Anciano de 80 o más Años , Células Cultivadas , Neoplasias Colorrectales/mortalidad , Pruebas Inmunológicas de Citotoxicidad , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura/genética , Humanos , Memoria Inmunológica , Masculino , Inestabilidad de Microsatélites , Repeticiones de Microsatélite , Valor Predictivo de las Pruebas , Pronóstico , Análisis de Supervivencia , TranscriptomaRESUMEN
The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with decreased IL15 expression, a higher risk of tumor recurrence, and reduced patient survival. Decreased IL15 expression affected the local proliferation of B and T lymphocytes. Patients with proliferating B and T cells at the invasive margin and within the tumor center had significantly prolonged disease-free survival. These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL15. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor, and the importance of local active lymphocyte proliferation for patient survival.