PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen

Abstract

The spleen is an important site of hematopoietic stem/progenitor cell (HSPC) preconditioning and tumor-promoting myeloid cell generation in cancer, but the regulatory mechanism remains unclear. Here, we found that PKR-like endoplasmic reticulum kinase (PERK) mediated HSPC reprogramming into committed MDSC precursors in the spleen via PERK–ATF4–C/EBPβ signaling. Pharmacological and genetic inhibition of this pathway in murine and human HSPCs prevented their myeloid descendant cells from becoming MDSCs even with subsequent exposure to tumor microenvironment (TME) factors. In mice, the selective delivery of PERK antagonists to the spleen was not only sufficient but more effective than the tumor-targeted strategy in preventing MDSC activation in the tumor, leading to profound TME reshaping and tumor regression. Clinically, HSPCs in the spleen of cancer patients exhibit increased PERK signaling correlated with enhanced myelopoiesis. Our findings indicate that PERK-mediated HSPC preconditioning plays a crucial role in MDSC generation, suggesting novel spleen-targeting therapeutic opportunities for restraining the tumor-promoting myeloid response at its source.

Hematologic dysfunction in cancer: Mechanisms, effects on antitumor immunity, and roles in disease progression

“…Furthermore, PERK activation was observed in splenic HSPCs of patients with hepatocellular carcinoma and gastric cancer, and correlated with myeloid cell abundance. Overall, this indicates PERK as a promising drug target to prevent cancer immune evasion ( 51 ). This study also supports the specialized role of the splenic environment and the aberrant signaling events in splenic HSPCs as drivers of cancer associated myelopoiesis in hepatocellular carcinoma ( 51 ), although it remains to be explored to what extent the same mechanisms apply in other cancer models.…”

“…These studies further demonstrated the accumulation of splenic HSPCs and myeloid progenitors in human cancer patients ( 49 , 50 ), which correlated with myeloid cell expansion and in gastric cancer cohorts also with poor prognosis ( 50 ). Recently scRNA-seq of HSPCs (Lin - cKit + Sca1 + ) from the spleen and bone marrow in the orthotopic Hepa1-6 HCC mouse model demonstrated a strong expansion of myeloid biased cells in the spleen, resembling the MPP3 subset of bone marrow HSPCs, with the expression of many genes indicative of myeloid lineage priming ( 51 ). In contrast, in mice transgenic for a photoconvertible protein KikGR that allows to ‘timestamp’ myeloid cells with surgery and violet light exposure, subcutaneous inoculation of syngeneic LLC lung adenocarcinoma cells demonstrated that the bone marrow rather than spleen remained the major source of monocytes, including those infiltrating the tumors ( 52 ).…”

“…Further studies in an orthotopic Hepa1-6 hepatoma mouse model using a micro-osmotic pump for targeted PERK inhibitor delivery demonstrated that the delivery of the inhibitor to the spleen rather than the tumor was most effective at limiting cancer associated myelopoiesis, and resulted in enhanced tumor infiltration by IFNγ + CD8 T cells and delayed disease progression ( 51 ). Mouse HSPCs co-cultured with splenic stromal cells from tumor bearing mice or human cord blood HSPCs cultured with IL-6 and other cytokines demonstrated activation of PERK and its downstream signaling mediators, and gave rise to neutrophils with immunosuppressive properties in a PERK dependent manner ( 51 ). Furthermore, PERK activation was observed in splenic HSPCs of patients with hepatocellular carcinoma and gastric cancer, and correlated with myeloid cell abundance.…”

“…In contrast, studies addressing the mechanisms of accelerated breast cancer progression following myocardial infarction (MI), using either MMTV-PyMT transgenic mice or mice inoculated orthotopically with a mammary cancer cell line E0771, demonstrated an expansion of Ly6C hi monocytes in mouse bone marrow, blood, and tumor tissues. Such Ly6C hi monocytes had altered chromatin accessibility (ATAC-seq) at the genes engaged in ER-stress response, UPR, and inflammation ( 115 ), which are also implicated in the induction of aberrant myelopoiesis in other cancer models ( 51 , 101 ). Depletion of the Ly6C hi cells abrogated the MI-induced increase in breast cancer progression, supporting their pathogenic activity ( 115 ).…”

The “Yin and Yang” of Unfolded Protein Response in Cancer and Immunogenic Cell Death

“…In glioblastoma where IRE1 somatic mutations have been linked to shorter patient survival, the IRE1 signaling dictates two distinct tumor phenotypes, with XBP1s driving the protumorigenic program, while RIDD activity attenuates it [ 121 ]. Likewise, constitutive activation of the PERK pathway has been linked to carcinogenesis and metastasis in different cancer types [ 122 , 123 ] (reviewed in: [ 124 ]). However, depending on the gene dose, PERK can function as either a tumor suppressor (when haploinsufficient) or a proadaptive tumor promoter [ 125 ].…”