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lmproving colorectal cancer immunotherapy by enhancing migration and cytotoxicity of DOT cells
Publication . Carreira, Mariana Alexandre; Blanco-Domínguez, Rafael; Cabral, Maria de Guadalupe
Immunotherapy has emerged as a promising therapeutic approach for a myriad of solid tumors, although its effectiveness against colorectal cancer (CRC) patients remains limited. Most CRC tumors harbor mechanisms that minimize MHC-class I presentation and neoantigen generation, compromising the recognition of tumor cells by conventional αβ T cells. Conversely, γδ T cells display a strong anti-tumor activity, independent of MHC-mediated antigen presentation and neoantigen burden. Despite their discrete levels in the blood, Vδ1+ γδ T cells exhibit a natural tropism to the gut and tumors, rendering them appealing targets for CRC immunotherapy. Due to their unique properties, the laboratory developed a Vδ1+ γδ T cell-based adoptive cell therapy, named Delta One T (DOT) cells, with proven tumoricidal potential against hematological malignancies and CRC. Previous work has shown that DOT cells control tumor growth in an orthotopic (intercaecal) xenograft model of human CRC with SW620 cells. Nevertheless, the mechanism underlying DOT-cell infiltration into CRC remains unknown. Here, by using migration assays we confirmed that DOT cells migrate towards SW620 cells and patient-derived CRC specimens in a dose-dependent manner. Strikingly, in our CRC xenograft model, DOT cells were found to selectively infiltrate the tumor, while sparing healthy gut tissue. Flow cytometry analysis unveiled CXCR3 as the most highly expressed chemokine receptor on DOT cells, aligning with the presence of CXCL9 and CXCL10 (CXCR3 ligands) in SW620 cell supernatants. Additionally, analysis of The Cancer Genome Atlas identified CXCR3 ligands as overexpressed in primary samples derived from colon and rectal cancer when compared with healthy colon and healthy rectum samples, respectively. Subsequent experiments demonstrated that CXCL10 effectively attracts DOT cells, whereas CXCR3 inhibition impairs DOT cell migration towards CRC both in vitro and in vivo. In addition, we characterized that tumor-infiltrating DOT cells exhibiting a dysfunctional phenotype, elevated the expression of the inhibitory receptors TIGIT, PD-1, and TIM3 after reaching the tumors. Dual blockade of TIGIT and PD-1 emerged as the most potent strategy for restoring and enhancing DOT cell tumoricidal activity in our CRC xenograft model. This thesis provides novel insights into the migratory properties of DOT cells and explores new therapeutic strategies to enhance their cytotoxic functions in CRC.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
Concurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2020
Número da atribuição
PTDC/MED-ONC/6829/2020