Spatial biology reveals altered macrophage states in immunosuppressed non-melanoma skin cancer
(1) Naara S (2) Kochat V (3) Rao X (4) Arslan E (5) Saddawi-Konefka R (6) Satpati S (7) Garbarino J (8) Anderson JL (9) Gleber-Netto FO (10) Nagarajan P (11) Kerr TD (12) Akhter S (13) Li S (14) Fodor R (15) Koyfman SA (16) Yaniv D (17) Xie T (18) Glaun M (19) Bobian M (20) Padron WI (21) Ng C (22) Gunaratne PH (23) Thevasagayampillai S (24) Migden MR (25) Abbas HA (26) Reville PK (27) Tsai KY (28) McGrail DJ (29) Wang J (30) Myers JN (31) Gross ND (32) Rai K (33) Amit M
Naara, Kochat, and Rao et al. compared the TIMEs of immunocompetent non-melanoma skin cancer (NMSC) patients and systemically immunosuppressed (IS) patients (organ transplant recipients or hematological cancer) who had reduced survival. Spatial multiomics revealed immunosuppression did not correlate with overall immune cell abundance, but with decreased numbers of intratumoral CD68+ macrophages, decreased T cell repertoire diversity, altered APC distribution, function, and cell–cell interactions, and distinct fibroblast-rich niches. Specific TIME niches showed distinct epigenetic regulation of transcription factors linked to poor immune function in IS patients.
Contributed by Katherine Turner
(1) Naara S (2) Kochat V (3) Rao X (4) Arslan E (5) Saddawi-Konefka R (6) Satpati S (7) Garbarino J (8) Anderson JL (9) Gleber-Netto FO (10) Nagarajan P (11) Kerr TD (12) Akhter S (13) Li S (14) Fodor R (15) Koyfman SA (16) Yaniv D (17) Xie T (18) Glaun M (19) Bobian M (20) Padron WI (21) Ng C (22) Gunaratne PH (23) Thevasagayampillai S (24) Migden MR (25) Abbas HA (26) Reville PK (27) Tsai KY (28) McGrail DJ (29) Wang J (30) Myers JN (31) Gross ND (32) Rai K (33) Amit M
Naara, Kochat, and Rao et al. compared the TIMEs of immunocompetent non-melanoma skin cancer (NMSC) patients and systemically immunosuppressed (IS) patients (organ transplant recipients or hematological cancer) who had reduced survival. Spatial multiomics revealed immunosuppression did not correlate with overall immune cell abundance, but with decreased numbers of intratumoral CD68+ macrophages, decreased T cell repertoire diversity, altered APC distribution, function, and cell–cell interactions, and distinct fibroblast-rich niches. Specific TIME niches showed distinct epigenetic regulation of transcription factors linked to poor immune function in IS patients.
Contributed by Katherine Turner
ABSTRACT: Immunosuppressed patients with non-melanoma skin cancer experience worse clinical outcomes, yet the tumor immune microenvironment associated with systemic immunosuppression remains incompletely defined. Using integrated single-cell, spatial transcriptomic, multiplex immunofluorescence, and spatial epigenomic profiling across immunocompetent and immunosuppressed tumors, we found that overall immune-cell composition was largely preserved despite differences in immune-cell distribution, spatial organization, and T cell clonality. Immunosuppressed tumors demonstrated reduced intratumoral macrophage densities, decreased T cell clonal diversity, altered antigen-presenting cell and T cell spatial interactions, and distinct fibroblast- and macrophage-associated spatial niches. Multi-cohort validation across complementary spatial and single-cell platforms identified consistent alterations in innate-adaptive immune organization in immunosuppressed tumors. Together, these findings define spatial and functional remodeling of the tumor immune microenvironment under systemic immunosuppression and provide a framework for future therapeutic investigation in high-risk patients.
Author Info:
(1) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) MD Anderson Epigenomics Therapy Initiative, Department of Genomic
Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Bioinformatics and Computational Biology, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Otolaryngology-Head and Neck Surgery, Gleiberman Head and Neck Cancer Center, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. (6) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) AtlasXomics, Pierce Laboratory, 290 Congress Ave, New Haven, CT, USA. (8) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: fonetto@mdanderson.org. (10) Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: pnagarajan@mdanderson.org. (11) Department of Cancer Sciences, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH, USA. (12) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA. (15) Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA. (16) Department of Otolaryngology, Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel. (17) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) AtlasXomics, Pierce Laboratory, 290 Congress Ave, New Haven, CT, USA. (22) Department of Biology and Biochemistry, University of Houston Sequencing Core, University of Houston, Houston, TX, USA; Department of Molecular and Cellular Biology, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX , USA. (23) Department of Biology and Biochemistry, University of Houston Sequencing Core, University of Houston, Houston, TX, USA; Department of Molecular and Cellular Biology, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX , USA. (24) Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mrmigden@mdanderson.org. (25) Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (28) Department of Cancer Sciences, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH, USA. Electronic address: mcgraid@ccf.org. (29) Department of Bioinformatics and Computational Biology, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (32) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: krai@mdanderson.org. (33) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Cancer Neuroscience Program, UT MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mamit@mdanderson.org.
