Tumor-resident T cells and dendritic cells form an in situ archetype during immunotherapy response in melanoma
(1) Di Pietro A (2) Au L (3) Crock P (4) Thio N (5) Pizzolla A (6) Nguyen TN (7) Macdonald S (8) Chalmers H (9) Zhu R (10) Airaghi A (11) Molden-Hauer T (12) Bacac M (13) Schwalie P (14) Schlenker R (15) Levesque MP (16) Mailer S (17) Barnes-Cullen K (18) Winch K (19) Chan J (20) Yeung GA (21) Spain L (22) Rao AD (23) Sandhu S (24) Gyorki DE (25) McArthur GA (26) Mackay LK (27) Neeson PJ
Pietro and Au et al. profiled melanoma lymph node metastases from untreated, ICB-resistant, and ICB-responsive patients using flow cytometry, mIHC, and single-cell transcriptomics to dissect tumor-resident (TR) T cell niches. ICB-responsive tumors were enriched for clonally expanded, cytotoxic CD8⁺ TR cells and cytotoxic/helper CD4⁺ TR cells within an immune-activated microenvironment, whereas ICB-resistant tumors displayed chronic IFNγ signaling, exhausted T cell states, and impaired clonal diversification. Spatial analyses identified CD8⁺ TRs, CD4⁺ TRs, and DC3s forming in situ immune triads as an essential feature of ICB responders.
Contributed by Shishir Pant
(1) Di Pietro A (2) Au L (3) Crock P (4) Thio N (5) Pizzolla A (6) Nguyen TN (7) Macdonald S (8) Chalmers H (9) Zhu R (10) Airaghi A (11) Molden-Hauer T (12) Bacac M (13) Schwalie P (14) Schlenker R (15) Levesque MP (16) Mailer S (17) Barnes-Cullen K (18) Winch K (19) Chan J (20) Yeung GA (21) Spain L (22) Rao AD (23) Sandhu S (24) Gyorki DE (25) McArthur GA (26) Mackay LK (27) Neeson PJ
Pietro and Au et al. profiled melanoma lymph node metastases from untreated, ICB-resistant, and ICB-responsive patients using flow cytometry, mIHC, and single-cell transcriptomics to dissect tumor-resident (TR) T cell niches. ICB-responsive tumors were enriched for clonally expanded, cytotoxic CD8⁺ TR cells and cytotoxic/helper CD4⁺ TR cells within an immune-activated microenvironment, whereas ICB-resistant tumors displayed chronic IFNγ signaling, exhausted T cell states, and impaired clonal diversification. Spatial analyses identified CD8⁺ TRs, CD4⁺ TRs, and DC3s forming in situ immune triads as an essential feature of ICB responders.
Contributed by Shishir Pant
ABSTRACT: Tumor-resident (TR) T cells, known as tissue-resident memory (TRM) T cells in mice, play a central role in melanoma immunosurveillance, yet their contribution to immune checkpoint inhibitor (ICI) therapy has not been comprehensively explored. We performed spatial and single-cell profiling on 32 metastatic melanoma lymph node samples, from treatment-naïve, ICI-resistant and ICI-responsive patients. Here we show that tumor areas in ICI-responders were enriched for both CD8+ and CD4+ TR. CD8+ TR cells were clonally expanded, and both CD8+ and CD4+ TR cells upregulated cytotoxicity-related gene expression, suggesting functional anti-tumor immunity. Conversely, ICI-resistant tumors displayed chronic IFN-γ response pathways, linked to T cell exhaustion. We further identified a spatially organized immune triad composed of CD8⁺ TR, CD4⁺ TR, and type-3 dendritic cells (DC3) that is exclusive to responding tumors. These findings define coordinated cellular interactions within the tumor microenvironment that underpin successful immunotherapy and provide a framework for spatial biomarkers of response.
Author Info:
(1) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Austra
lia. (2) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (3) Bioinformatics, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (4) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Bioinformatics, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (5) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (10) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (12) Roche Innovation Center, Zurich, Switzerland. (13) Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland. (14) Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland. (15) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (16) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Melanoma Research Victoria, Melbourne, VIC, Australia. Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (17) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Melanoma Research Victoria, Melbourne, VIC, Australia. Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (18) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Melanoma Research Victoria, Melbourne, VIC, Australia. Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (19) Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (20) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (21) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (22) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (23) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (24) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (25) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Melanoma Research Victoria, Melbourne, VIC, Australia. Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (26) Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. (27) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. paul.neeson@petermac.org. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. paul.neeson@petermac.org.
