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
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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, Aishwarya; Draghi, Arianna; Papp, Krisztian; Borch, Troels Holz; Nielsen, Morten; Westergaard, Marie Christine Wulff; Andersen, Rikke; Schina, Aimilia; Bol, Kalijn Fredrike; Chamberlain, Christopher Aled; Presti, Mario; Met, Özcan; Harbst, Katja; Lauss, Martin; Soraggi, Samuele; Csabai, Istvan; Szállási, Zoltán; Jönsson, Göran; Svane, Inge Marie; Donia, Marco.
I: Cancers, Bind 12, Nr. 11, 3344, 2020, s. 1-15.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - 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
AU - Gokuldass, Aishwarya
AU - Draghi, Arianna
AU - Papp, Krisztian
AU - Borch, Troels Holz
AU - Nielsen, Morten
AU - Westergaard, Marie Christine Wulff
AU - Andersen, Rikke
AU - Schina, Aimilia
AU - Bol, Kalijn Fredrike
AU - Chamberlain, Christopher Aled
AU - Presti, Mario
AU - Met, Özcan
AU - Harbst, Katja
AU - Lauss, Martin
AU - Soraggi, Samuele
AU - Csabai, Istvan
AU - Szállási, Zoltán
AU - Jönsson, Göran
AU - Svane, Inge Marie
AU - Donia, Marco
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Immunotherapy
KW - Tumor microenvironment
KW - Tumor-infiltrating lymphocytes
U2 - 10.3390/cancers12113344
DO - 10.3390/cancers12113344
M3 - Journal article
C2 - 33198174
AN - SCOPUS:85096660297
VL - 12
SP - 1
EP - 15
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 11
M1 - 3344
ER -
ID: 252679590