Combined Detection of CD137 and Type 1 Functions Improves Identification and Characterization of the Activated T Lymphocyte Repertoire

Draghi, Arianna; Gokuldass, Aishwarya; Chamberlain, Christopher Aled; Radic, Haja Dominike; Svane, Inge Marie; Donia, Marco

doi:10.1093/annonc/mdz450.001

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“…Here, although TNF and IFNγ were also used in vitro in all samples due to their high signal-to-noise ratio in activated TILs (barely detectable in TILs alone —significantly upregulated in a variable proportion of TILs recognizing autologous tumor cells), CD137 (encoded by the gene TNFRSF9 ) upregulation was not included in the in vitro analyses. Indeed, the samples used in the study were obtained over a decade, whereas we only recently began to use CD137 as additional tumor-specific (but function-agnostic) T cell activation marker, and confirmed that a proportion accounting for ~20% of the total CD8 + tumor-reactive repertoire may be identified by expression of CD137, but not TNF, IFNγ or CD107a [ 48 ]. As CD137 may be constitutively expressed on CD4 + regulatory T cells [ 49 ], we carried out additional analyses on intratumor CD4 + T cells using TNF and IFNG only ( Figure S5 ).…”

Section: Methodsmentioning

confidence: 99%

Qualitative Analysis of Tumor-Infiltrating Lymphocytes across Human Tumor Types Reveals a Higher Proportion of Bystander CD8+ T Cells in Non-Melanoma Cancers Compared to Melanoma

Gokuldass

Draghi

Papp

et al. 2020

Cancers

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Background: Human intratumoral T cell infiltrates can be defined by quantitative or qualitative features, such as their ability to recognize autologous tumor antigens. In this study, we reproduced the tumor-T cell interactions of individual patients to determine and compared the qualitative characteristics of intratumoral T cell infiltrates across multiple tumor types. Methods: We employed 187 pairs of unselected tumor-infiltrating lymphocytes (TILs) and autologous tumor cells from patients with melanoma, renal-, ovarian-cancer or sarcoma, and single-cell RNA sequencing data from a pooled cohort of 93 patients with melanoma or epithelial cancers. Measures of TIL quality including the proportion of tumor-reactive CD8+ and CD4+ TILs, and TIL response polyfunctionality were determined. Results: Tumor-specific CD8+ and CD4+ TIL responses were detected in over half of the patients in vitro, and greater CD8+ TIL responses were observed in melanoma, regardless of previous anti-PD-1 treatment, compared to renal cancer, ovarian cancer and sarcoma. The proportion of tumor-reactive CD4+ TILs was on average lower and the differences less pronounced across tumor types. Overall, the proportion of tumor-reactive TILs in vitro was remarkably low, implying a high fraction of TILs to be bystanders, and highly variable within the same tumor type. In situ analyses, based on eight single-cell RNA-sequencing datasets encompassing melanoma and five epithelial cancers types, corroborated the results obtained in vitro. Strikingly, no strong correlation between the proportion of CD8+ and CD4+ tumor-reactive TILs was detected, suggesting the accumulation of these responses in the tumor microenvironment to follow non-overlapping biological pathways. Additionally, no strong correlation between TIL responses and tumor mutational burden (TMB) in melanoma was observed, indicating that TMB was not a major driving force of response. No substantial differences in polyfunctionality across tumor types were observed. Conclusions: These analyses shed light on the functional features defining the quality of TIL infiltrates in cancer. A significant proportion of TILs across tumor types, especially non-melanoma, are bystander T cells. These results highlight the need to develop strategies focused on the tumor-reactive TIL subpopulation.

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Section: Methodsmentioning

confidence: 99%