Perivascular macrophages restrict CXCR4-dependent accumulation of stem-like CD8+ T cells in tumors and limit chemotherapy efficacy
(1) Cheung TS (2) Sarkar J (3) Yang DD (4) Feehan KT (5) Lovell WPM (6) Bahri M (7) Boad J (8) Macmorland W (9) Weitsman G (10) Caipa Garcia AL (11) Anstee JE (12) Bornemann L (13) Jones B (14) Kallayil AM (15) Dhami P (16) Ng T (17) Arnold JN
Cheung et al. showed that the onset of antitumor immunity in murine breast cancer models following cytotoxic chemotherapy (CCT) and loss of perivascular (Pv) TAM-derived heme oxygenase-1 activity was characterized by tumoral accumulation and differentiation of clonally diverse stem-like TCF1+PD-1+CD8+ T cells to tumor-reactive TCF1-CD8+ effector T cells. Their accumulation in the TIME was CXCR4-dependent and associated with CCT-induced expansion of proliferating Pv CXCL12+CD34+ cancer-associated fibroblasts. In human breast cancer, more favorable clinical outcomes post-CCT were associated with a high stem-like CD8+ T cell gene signature.
Contributed by Paula Hochman
(1) Cheung TS (2) Sarkar J (3) Yang DD (4) Feehan KT (5) Lovell WPM (6) Bahri M (7) Boad J (8) Macmorland W (9) Weitsman G (10) Caipa Garcia AL (11) Anstee JE (12) Bornemann L (13) Jones B (14) Kallayil AM (15) Dhami P (16) Ng T (17) Arnold JN
Cheung et al. showed that the onset of antitumor immunity in murine breast cancer models following cytotoxic chemotherapy (CCT) and loss of perivascular (Pv) TAM-derived heme oxygenase-1 activity was characterized by tumoral accumulation and differentiation of clonally diverse stem-like TCF1+PD-1+CD8+ T cells to tumor-reactive TCF1-CD8+ effector T cells. Their accumulation in the TIME was CXCR4-dependent and associated with CCT-induced expansion of proliferating Pv CXCL12+CD34+ cancer-associated fibroblasts. In human breast cancer, more favorable clinical outcomes post-CCT were associated with a high stem-like CD8+ T cell gene signature.
Contributed by Paula Hochman
ABSTRACT: The perivascular (Pv) niche coordinates immune-stromal interactions that facilitate cancer progression. Pharmacological inhibition or genetic inactivation of the enzyme heme oxygenase-1 (HO-1) in LYVE-1(+) Pv tumor-associated macrophages (PvTAMs) synergizes with cytotoxic chemotherapy (CCT) to achieve immunological tumor control in murine breast cancer models. We investigated the tumor microenvironment (TME) during the transition to immunological control and identified an increase in stem-like TCF1(+)PD-1(+)CD8(+) T cells and enrichment of tumor-selective effector T cells. Stem-like CD8(+) T cells were clonally diverse and rapidly acquired a TCF1(-) differentiated phenotype in the TME. Their tumor accumulation depended on CXCR4 and was associated with a treatment-induced expansion of proliferating CXCL12(+)CD34(+) Pv cancer-associated fibroblasts (CAFs). In human breast cancer, greater abundance of the stem-like CD8(+) T cell program was associated with improved outcomes following CCT. These findings identify PvTAM HO-1 activity as a regulator of a stromal-stem-like T cell axis that limits chemotherapy efficacy and anti-tumor immunity.
Author Info:
(1) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (2) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL
, UK. (3) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (4) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (5) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (6) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (7) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (8) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (9) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (10) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (11) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (12) Miltenyi Biotec B.V. & Co. KG, Friedrich-Ebert-Stra§e 68, 51429 Bergisch Gladbach, Germany. (13) Genome Centre, Blizard Institute, Queen Mary University of London, London E1 2AT, UK. (14) Genomics Research Platform, Advanced Therapies Centre, Guy's Hospital, King's College London, London SE1 9RT, UK. (15) Genomics Research Platform, Advanced Therapies Centre, Guy's Hospital, King's College London, London SE1 9RT, UK. (16) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (17) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. Electronic address: james.arnold@kcl.ac.uk.
Citation: Cell Stem Cell 2026 Nov 4 Epub11/04/2026
