Rachel Wolters

Abstract Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs) 1,2 , partly because there are immunosuppressive myeloid cells in tumours 3,4 . However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts ( SPP1 hi -TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8 + T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1 hi -TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1 hi -TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1 hi -TAM-mediated immunosuppression in CD8 + T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1 hi -TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1 hi -TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.

Cx3cr1+ monocyte-derived macrophages (moMacs) are recruited to tissues after injury and are known to have profibrotic effects, but the cell-cell interactions and specific pathways that regulate this polarization and function are incompletely understood. Here we investigate the role of moMac-derived Pdgfa in bleomycin-induced lung fibrosis in mice. Deletion of Pdgfa with Cx3cr1-CreERT2 decreased bleomycin-induced lung fibrosis. Among a panel of in vitro macrophage polarizing stimuli, robust induction of Pdgfa was noted with IL10 in both mouse and human moMacs. Likewise, analysis of single-cell data revealed high expression of the receptor IL10RA in moMacs from human fibrotic lungs. Studies with IL10-GFP mice revealed that IL10-expressing cells were increased after injury in mice and colocalized with moMacs. Notably, deletion of IL10ra with Csf1r-Cre: IL10ra fl/fl mice decreased both Pdgfa expression in moMacs and lung fibrosis. Taken together, these findings reveal a novel, IL10-dependent mechanism of macrophage polarization leading to fibroblast activation after injury.

As Migrants and as ImmigrantsAfrican Americans Search for Land and Liberty in the Great Plains, 1890–1912 Rachel Wolters (bio) Keywords immigration, Oklahoma, racism, transnationalism, western Canada In March 1913 Sally Carothers and her family made the journey from Weleetka, Oklahoma, to Edmonton, Canada, following the path that hundreds of African Americans from Oklahoma took to western Canada in the early twentieth century. Sally immediately felt the isolation of the western Great Plains in Canada: there were no churches or schools when her family settled on their homestead. But she also knew that her parents were not concerned about the absence of these institutions, because they had migrated to find freedom. When in 1907 Oklahoma became the forty-sixth state with the merging of Oklahoma and Indian Territories, white Oklahomans, influenced by southern traditions of racial exclusion, immediately implemented Jim Crow legislation. As a result, hundreds of blacks sought freedom in Canada. “All they had in mind,” Sally recalled of her parents, “was coming to a country where we could have freedom—free to be a human being; free to be able to cope with any white person,” adding, “I never heard my dad say he regretted coming here.”1 Freedom for many African Americans meant not only being “able to cope with any white person” but also having land of your own. And African Americans traveled north to Canada in search of land for their families. Walker Beaver was thirteen when his family left Oklahoma on March 21, 1910, for Athabasca, Alberta. His family traveled with a large group of people who brought all their household goods with them on a chartered freight car. Walker remembered that some people even brought their horses and wagons with them. These Oklahoma farmers were part of a larger migration of people leaving the United States for the Canadian prairies in search of cheap, productive land. As Walker recalled, “In Kansas City there was an agent telling people about Canada—the land of milk and honey—for ten dollars you could buy a hundred and sixty acres of land, a homestead. So people thought [End Page 333] they were getting a fortune, you understand, that’s why they came.”2 For African Americans in Oklahoma, Canada represented an opportunity for both freedom and land. Land and Liberty The twin themes of land and liberty that drove African Americans from the South to Oklahoma and then onward to Canada in the late nineteenth and early twentieth centuries was a transnational migration of people and values. Both political policies and cultural attitudes in the United States and Canada affected the movement of blacks. African Americans traveled by the thousands to Oklahoma in the 1890s in order to acquire land during the opening of Indian Territory to settlers. These black settlers held hopes for the establishment of an all-black state and for freedom from the hardening of Jim Crow laws and discrimination in the Southern states. Some built all-black towns; others lived in towns and communities with whites. But the land runs brought many more whites than blacks to the territories, and the dream of an all-black state soon disappeared. Even worse for African Americans were the racist sentiments held by white migrants, who sought to ensure that Oklahoma resembled the Jim Crow South they had left. At the same time that blacks in Oklahoma faced the tightening of Jim Crow restrictions, the government of Canada advertised for American farmers to settle on the western prairie provinces, mostly Alberta and Saskatchewan. The Canadian government had admitted Alberta and Saskatchewan as provinces in 1905 and hoped to fill the plains with farmers who would work the land and boost Canadian agriculture. But only a few eastern Canadians ventured west, and the Canadian government decided to advertise for immigrants from the United States and European nations, including Great Britain. Canadians saw American farmers as ideal immigrants because they were already familiar with the cultivation of crops such as wheat that flourished on the Canadian prairies. The Canadian Immigration Branch established offices in numerous American cities and relied on newspapers and agents to broadcast abundant cheap land and plentiful opportunities in western Canada. Appealing to...

While immune checkpoint inhibition (CPI) has reshaped cancer treatment, the majority of patients with cancer do not benefit from this approach, which can also cause immune-related adverse events. Induction of IFN-γ responses is thought be necessary for antitumor immunity, but growing evidence also implicates IFN-γ as a tumor-intrinsic mediator of CPI resistance. CPI-induced IFN-γ mediates activation-induced cell death in T cells as an immune-intrinsic mechanism of resistance. In this study, we found that transient block of IFN-γ signaling through administration of the JAK1 inhibitor ABT-317 enhanced antitumor T cell responses with CPI in preclinical models. Importantly, sequential but not concomitant ABT-317 treatment led to significantly reduced toxicity and improved tumor efficacy. Sequential treatment reduced activation-induced T cell death and enhanced expansion of tumor-reactive T cell subsets with increased effector function in vivo and ex vivo. Only CPI in combination with ABT-317 also enhanced memory responses by protecting mice from tumor rechallenge. These results demonstrate that JAK inhibition within a discrete time window following CPI addresses an immune-intrinsic mechanism of therapeutic resistance.