Magen and Hamon et al. analyzed surgically resected tumor lesions and matched, non-involved adjacent liver tissues from HCC patients with T cell-rich tumors to identify molecular correlates of response to neoadjuvant ICB therapy. PD-1hi effector CD8+ T cells and CXCL13+ TH cells were preferentially clonally expanded in tumors of responders, whereas a subset of T cell-rich tumors that failed to respond to anti-PD-1 showed increases in PD-1hi terminal CD8+ T cells and Tregs. T cell clones that expanded upon PD-1 blockade were present in tumor lesions before treatment, and PD-1hi progenitor CD8+ T cells were enriched in close proximity to mregDC/CXCL13+ TH niches in responders.
Contributed by Shishir Pant
ABSTRACT: Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13(+)CH25H(+)IL-21(+)PD-1(+)CD4(+) T helper cells ("CXCL13(+) T(H)") and Granzyme K(+) PD-1(+) effector-like CD8(+) T cells, whereas terminally exhausted CD39(hi)TOX(hi)PD-1(hi)CD8(+) T cells dominated in nonresponders. CD4(+) and CD8(+) T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1(+)TCF-1(+) (Progenitor-exhausted) CD8(+) T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8(+) T cell differentiation occurs upon ICB. We found that these Progenitor CD8(+) T cells interact with CXCL13(+) T(H) within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". These results suggest that discrete intratumoral niches that include mregDC and CXCL13(+) T(H) control the differentiation of tumor-specific Progenitor exhasuted CD8(+) T cells following ICB.
Author Info: (1) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, N
Author Info: (1) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Department of Oncology & Angiogenesis, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (4) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (17) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (18) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (19) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (20) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (21) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (22) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (23) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 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