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Stroma-infiltrating T cell spatiotypes define immunotherapy outcomes in adolescent and young adult patients with melanoma.

ABSTRACT: The biological underpinnings of therapeutic resistance to immune checkpoint inhibitors (ICI) in adolescent and young adult (AYA) melanoma patients are incompletely understood. Here, we characterize the immunogenomic profile and spatial architecture of the tumor microenvironment (TME) in AYA (aged ≤ 30 years) and older adult (aged 31-84 years) patients with melanoma, to determine the AYA-specific features associated with ICI treatment outcomes. We identify two ICI-resistant spatiotypes in AYA patients with melanoma showing stroma-infiltrating lymphocytes (SILs) that are distinct from the adult TME. The SIL^high subtype was enriched in regulatory T cells in the peritumoral space and showed upregulated expression of immune checkpoint molecules, while the SIL^low subtype showed a lack of immune activation. We establish a young immunosuppressive melanoma score that can predict ICI responsiveness in AYA patients and propose personalized therapeutic strategies for the ICI-resistant subgroups. These findings highlight the distinct immunogenomic profile of AYA patients, and individualized TME features in ICI-resistant AYA melanoma that require patient-specific treatment strategies.

SUBMITTER: Bai X

PROVIDER: S-EPMC11002019 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Stroma-infiltrating T cell spatiotypes define immunotherapy outcomes in adolescent and young adult patients with melanoma.

Bai Xinyu X Attrill Grace H GH Gide Tuba N TN Ferguson Peter M PM Nahar Kazi J KJ Shang Ping P Vergara Ismael A IA Palendira Umaimainthan U da Silva Ines Pires IP Carlino Matteo S MS Menzies Alexander M AM Long Georgina V GV Scolyer Richard A RA Wilmott James S JS Quek Camelia C

Nature communications 20240408 1

The biological underpinnings of therapeutic resistance to immune checkpoint inhibitors (ICI) in adolescent and young adult (AYA) melanoma patients are incompletely understood. Here, we characterize the immunogenomic profile and spatial architecture of the tumor microenvironment (TME) in AYA (aged ≤ 30 years) and older adult (aged 31-84 years) patients with melanoma, to determine the AYA-specific features associated with ICI treatment outcomes. We identify two ICI-resistant spatiotypes in AYA pat ...[more]

PMID: 38589406

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Project description:ImportanceCancer diagnosis and treatment may adversely affect reproductive outcomes among female cancer survivors.ObjectiveTo compare the birth outcomes of adolescent and young adult cancer survivors (AYA [diagnosed at ages 15-39 years]) with those of women without a cancer diagnosis.Design, setting, and participantsThe North Carolina Central Cancer Registry (CCR) was used to identify female AYA cancer survivors diagnosed from January 2000 to December 2013; CCR records were linked to statewide birth certificate files from January 2000 to December 2014 to identify postdiagnosis live births to AYA survivors (n = 2598). A comparison cohort of births to women without a recorded cancer diagnosis was randomly selected from birth certificate files (n = 12 990) with frequency matching on maternal age and year of delivery.Main outcomes and measuresPrevalence of preterm birth, low birth weight, small-for-gestational-age births, cesarean delivery, and low Apgar score.ResultsOverall, 2598 births to AYA cancer survivors (mean [SD] maternal age, 31 [5] years) were included. Births to AYA cancer survivors had a significantly increased prevalence of preterm birth (prevalence ratio [PR], 1.52; 95% CI, 1.34-1.71), low birth weight (PR, 1.59; 95% CI, 1.38-1.83), and cesarean delivery (PR, 1.08; 95% CI, 1.01-1.14) relative to the comparison cohort of 1299. The higher prevalence of these outcomes was most concentrated among births to women diagnosed during pregnancy. Other factors associated with preterm birth and low birth weight included treatment with chemotherapy and a diagnosis of breast cancer, non-Hodgkin lymphoma, or gynecologic cancers. The prevalence of small-for-gestational-age births and low Apgar score (<7) did not differ significantly between groups.Conclusions and relevanceLive births to AYA cancer survivors may have an increased risk of preterm birth and low birth weight, suggesting that additional surveillance of pregnancies in this population is warranted. Our findings may inform the reproductive counseling of female AYA cancer survivors.

Project description:ImportanceDepression is a leading cause of disability. The timing and persistence of depression may be differentially associated with long-term mental health and psychosocial outcomes.ObjectiveTo examine if depression symptoms during early and middle childhood and adolescence and persistent depression symptoms are associated with impaired young adult outcomes independent of early risk factors.Design, setting, and participantsData for this prospective, longitudinal cohort study were from the Québec Longitudinal Study of Child Development, a representative population-based Canadian birth cohort. The cohort consists of infants born from October 1, 1997, to July 31, 1998. This is an ongoing study; data are collected annually or every 2 years and include those ages 5 months to 21 years. The end date for the data in this study was June 30, 2019, and data analyses were performed from October 4, 2022, to January 3, 2024.ExposuresDepression symptoms were assessed using maternal reports in early childhood (ages 1.5 to 6 years) from 1999 to 2004, teacher reports in middle childhood (ages 7 to 12 years) from 2005 to 2010, and self-reports in adolescence (ages 13 to 17 years) from 2011 to 2015.Main outcomes and measuresThe primary outcome was depression symptoms at age 20 years, and secondary outcomes were indicators of psychosocial functioning (binge drinking; perceived stress; not being in education, employment, or training; social support; and experiencing online harrasment) at age 21 years. All outcomes were self-reported. Adult outcomes were reported by participants at ages 20 and 21 years from 2017 to 2019. Risk factors assessed when children were aged 5 months old were considered as covariates to assess the independent associations of childhood and adolescent depression symptoms with adult outcomes.ResultsThe cohort consisted of 2120 infants. The analytic sample size varied from 1118 to 1254 participants across outcomes (56.85% to 57.96% female). Concerning the primary outcome, adjusting for early risk factors and multiple testing, depression symptoms during adolescence were associated with higher levels of depression symptoms (β, 1.08 [95% CI, 0.84-1.32]; P < .001 unadjusted and Bonferroni adjusted) in young adulthood. Concerning the secondary outcomes, depression symptoms in adolescence were only associated with perceived stress (β, 3.63 [95% CI, 2.66-4.60]; P < .001 unadjusted and Bonferroni adjusted), while both middle-childhood (β, -1.58 [95% CI, -2.65 to -0.51]; P = .003 unadjusted and P < .001 Bonferroni adjusted) and adolescent (β, -1.97 [95% CI, -2.53 to -1.41]; P < .001 unadjusted and Bonferroni adjusted) depression symptoms were associated with lower levels of social support. There were no associations for binge drinking; not being in education, employment, or training; or experiencing online harrasment.Conclusions and relevanceIn this cohort study of Canadian children and adolescents, childhood and adolescent depression symptoms were associated with impaired adult psychosocial functioning. Interventions should aim to screen and monitor children and adolescents for depression to inform policymaking regarding young adult mental health and psychosocial outcomes.

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Stroma-infiltrating T cell spatiotypes define immunotherapy outcomes in adolescent and young adult patients with melanoma.

Publications

Stroma-infiltrating T cell spatiotypes define immunotherapy outcomes in adolescent and young adult patients with melanoma.

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