Lin−CCR2+ hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade

Abstract

Immune checkpoint blockade using anti-PD-1 monoclonal antibodies has shown considerable promise in the treatment of solid tumors, but brain tumors remain notoriously refractory to treatment. In CNS malignancies that are completely resistant to PD-1 blockade, we found that bone marrow-derived, lineage-negative hematopoietic stem and progenitor cells (HSCs) that express C–C chemokine receptor type 2 (CCR2+) reverses treatment resistance and sensitizes mice to curative immunotherapy. HSC transfer with PD-1 blockade increases T-cell frequency and activation within tumors in preclinical models of glioblastoma and medulloblastoma. CCR2+HSCs preferentially migrate to intracranial brain tumors and differentiate into antigen-presenting cells within the tumor microenvironment and cross-present tumor-derived antigens to CD8+ T cells. HSC transfer also rescues tumor resistance to adoptive cellular therapy in medulloblastoma and glioblastoma. Our studies demonstrate a novel role for CCR2+HSCs in overcoming brain tumor resistance to PD-1 checkpoint blockade and adoptive cellular therapy in multiple invasive brain tumor models.

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

“…Additionally, bone marrow-derived hematopoietic stem cells expressing type 2 C-C chemokine receptor (CCR2 + HSCs) preferentially migrate to tumor tissues and differentiate into APCs in the tumor microenvironment. The presentation of tumor-derived antigens to CD8 + T cells overcomes resistance to PD-1 checkpoint blockade [155]. Histone deacetylases (HDAC) are a therapeutic target for a variety of cancers.…”

Concise Review: Modulating Cancer Immunity with Hematopoietic Stem and Progenitor Cells

“…The findings described above by have been further expanded to include analyses in the combination therapy of HSPC transplant with PD‐1 checkpoint blockade . Interestingly, in brain tumors that are refractory to PD‐1 blockade, CCR2 + HSPC transfer mediates immunologic rejection of tumors that generates long‐term cures.…”

RNA-electroporated T cells for cancer immunotherapy

“…[105][106][107][108][109][110] Furthermore, the combination of T cell ACT with other forms of immune cell therapies has also yielded very promising results in preclinical studies. 111,112 Finally, for those combinatorial treatments to be implemented on a large scale for various cancer patient populations, issues pertaining to scale-up, automation, commercialization, intellectual property, costs/insurance reimbursements, and regulatory hurdles unique to cell therapy will need to be addressed. 1,113,114…”