RESUMEN
T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death 1-positive (PD-1+) Tim-3+CD8+ tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen-presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on Tim-3+ APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen-specific CD8+ T cells and PD-1+Tim-3+ CD8+ TILs isolated from patients with melanoma. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of CD8+ TILs in 2 melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not in CD8+ T cells impeded the trogocytosis of CD8+ TILs in vivo. Trogocytosed CD8+ T cells presented tumor peptide-major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism Tim-3 uses to limit antitumor immunity.
Asunto(s)
Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Melanoma , Animales , Linfocitos T CD8-positivos , Receptor 2 Celular del Virus de la Hepatitis A/genética , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Humanos , Linfocitos Infiltrantes de Tumor , Melanoma/patología , Ratones , Receptor de Muerte Celular Programada 1 , TrogocitosisRESUMEN
Ample evidence indicates that the gut microbiome is a tumor-extrinsic factor associated with antitumor response to anti-programmed cell death protein-1 (PD-1) therapy, but inconsistencies exist between published microbial signatures associated with clinical outcomes. To resolve this, we evaluated a new melanoma cohort, along with four published datasets. Time-to-event analysis showed that baseline microbiota composition was optimally associated with clinical outcome at approximately 1 year after initiation of treatment. Meta-analysis and other bioinformatic analyses of the combined data show that bacteria associated with favorable response are confined within the Actinobacteria phylum and the Lachnospiraceae/Ruminococcaceae families of Firmicutes. Conversely, Gram-negative bacteria were associated with an inflammatory host intestinal gene signature, increased blood neutrophil-to-lymphocyte ratio, and unfavorable outcome. Two microbial signatures, enriched for Lachnospiraceae spp. and Streptococcaceae spp., were associated with favorable and unfavorable clinical response, respectively, and with distinct immune-related adverse effects. Despite between-cohort heterogeneity, optimized all-minus-one supervised learning algorithms trained on batch-corrected microbiome data consistently predicted outcomes to programmed cell death protein-1 therapy in all cohorts. Gut microbial communities (microbiotypes) with nonuniform geographical distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts. Our findings shed new light on the complex interaction between the gut microbiome and response to cancer immunotherapy, providing a roadmap for future studies.
Asunto(s)
Microbioma Gastrointestinal , Melanoma , Microbiota , Bacterias/genética , Microbioma Gastrointestinal/genética , Humanos , Inmunoterapia/efectos adversos , Melanoma/tratamiento farmacológicoRESUMEN
BACKGROUND: Racial/ethnic minorities face known disparities in likelihood of kidney transplantation. These disparities may be exacerbated when coupled with ongoing substance use, a factor also reducing likelihood of transplantation. We examined whether race/ethnicity in combination with ongoing substance use predicted incidence of transplantation. METHODS: Patients were enrolled between March 2010 and October 2012 at the time of transplant evaluation. Substance use data were retrieved from transplant evaluations. Following descriptive analyses, the primary multivariable analyses evaluated whether, relative to the referent group (White patients with no substance use), racial/ethnic minority patients using any substances at the time of evaluation were less likely to receive transplants by the end of study follow-up (August 2020). RESULTS: Among 1152 patients, 69% were non-Hispanic White, 23% non-Hispanic Black, and 8% Other racial/ethnic minorities. White, Black, and Other patients differed in percentages of current tobacco smoking (15%, 26%, and 18%, respectively; P = 0.002) and illicit substance use (3%, 8%, and 9%; P < 0.001) but not heavy alcohol consumption (2%, 4%, and 1%; P = 0.346). Black and Other minority patients using substances were each less likely to receive transplants than the referent group (hazard ratios ≤0.45, P ≤ 0.021). Neither White patients using substances nor racial/ethnic minority nonusers differed from the referent group in transplant rates. Additional analyses indicated that these effects reflected differences in waitlisting rates; once waitlisted, study groups did not differ in transplant rates. CONCLUSIONS: The combination of minority race/ethnicity and substance use may lead to unique disparities in likelihood of transplantation. To facilitate equity, strategies should be considered to remove any barriers to referral for and receipt of substance use care in racial/ethnic minorities.
Asunto(s)
Trasplante de Riñón , Trastornos Relacionados con Sustancias , Minorías Étnicas y Raciales , Etnicidad , Disparidades en Atención de Salud , Humanos , Grupos Minoritarios , Estados Unidos/epidemiologíaRESUMEN
Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Resistencia a Antineoplásicos , Trasplante de Microbiota Fecal , Melanoma/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/terapia , Linfocitos T CD8-positivos/inmunología , Microbioma Gastrointestinal , Humanos , Interleucina-8/inmunología , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Células Mieloides/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
PURPOSE: Natural killer (NK) cells play a critical role in tumor immunosurveillance. Multiple activating and inhibitory receptors (IR) regulate NK-cell-mediated tumor control. The IR T-cell immunoglobulin and ITIM domain (TIGIT) and its counter-receptor CD226 exert opposite effects on NK-cell-mediated tumor reactivity. EXPERIMENTAL DESIGN: We evaluated the frequency, phenotype, and functions of NK cells freshly isolated from healthy donors and patients with melanoma with multiparameter flow cytometry. We assessed TIGIT and CD226 cell surface expression and internalization upon binding to CD155. We evaluated the role of IL15 and TIGIT blockade in increasing NK-cell-mediated cytotoxicity in vitro and in two mouse models. RESULTS: NK cells are present at low frequencies in metastatic melanoma, are dysfunctional, and downregulate both TIGIT and CD226 expression. As compared with TIGIT- NK cells, TIGIT+ NK cells exhibit higher cytotoxic capacity and maturation, but paradoxically lower cytotoxicity against CD155+ MHC class I-deficient melanoma cells. Membrane bound CD155 triggers CD226 internalization and degradation, resulting in decreased NK-cell-mediated tumor reactivity. IL15 increases TIGIT and CD226 gene expression by tumor-infiltrating NK cells (TiNKs) and, together with TIGIT blockade, increases NK-cell-mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. Specific deletion of TIGIT on transferred NK cells enhances the antimetastatic activity of IL15, while CD226 blockade decreases the effects of IL15 and TIGIT blockade. CONCLUSIONS: Our findings support the development of novel combinatorial immunotherapy with IL15 and TIGIT blockade to promote NK-cell-mediated destruction of MHC class I-deficient melanoma, which are refractory to CD8+ T-cell-mediated immunity.See related commentary by Pietra et al., p. 5274.