InVivoMAb anti-mouse CSF1

A hallmark of pancreatic cancer is an extensive fibroinflammatory stroma. Myeloid cells, including abundant macrophages, are a prevalent cellular component of the pancreatic cancer microenvironment and a key driver of immunosuppression. Identifying mechanisms of myeloid cell-driven immunosuppression is thus key to developing therapeutic approaches. Harnessing single-cell RNA sequencing data from human and murine tumors, we determined that tumor-infiltrating myeloid cells (including macrophages and granulocytes) have elevated expression of C-C motif chemokine receptor 1 (CCR1). To determine the functional role of CCR1, we generated oncogenic KRAS-based genetically engineered mouse models of pancreatic cancer, with or without the addition of a mutant form of the tumor suppressor Trp53 (KC and KPC, respectively), lacking CCR1 expression. CCR1 inactivation did not affect the formation of early lesions but delayed progression to cancer and resulted in prolonged survival. In these mice, macrophages lacking CCR1 had reduced expression of the immunosuppressive marker arginase 1. Loss of CCR1 also profoundly shifted the prevalent fibroblast population, inducing a pancreatic stellate cell-like phenotype. In two independent syngeneic orthotopic models, ablation or pharmacologic inhibition of CCR1 reduced tumor growth and increased CD8+ T-cell cytotoxic activity, sensitizing tumors to immunotherapy. Our data show that CCR1-expressing myeloid cells promote pancreatic cancer growth through modulation of the immune microenvironment and fibroblasts, indicating that CCR1 might be a suitable target for combination therapy.

Radiotherapy effectively treats colorectal cancer (CRC), but local recurrence remains common and abscopal effects-regression of tumors distant from irradiated sites-are rarely observed even with immune checkpoint inhibitors. Here we show that the protein kinase NEK8, highly expressed in CRC, promotes radioresistance by suppressing anti-tumor immunity. In radiation-resistant tumors, NEK8 phosphorylates lactate dehydrogenase A (LDHA), driving lactate overproduction. This metabolite promotes histone modifications that silence antigen presentation machinery, while extracellular lactate directly impairs CD8+ T cell function, collectively excluding CD8+ T cell from the tumor microenvironment. Pharmacological inhibition of NEK8 using CX6258 restores CD8+ T cell infiltration and enhances both local and systemic tumor control following radiotherapy. These findings establish NEK8 as a promising therapeutic target for overcoming radioresistance and inducing abscopal responses in CRC.

Successful pregnancy requires coordinated regulation between the innate and adaptive immune systems. Regulatory T (Treg) cells are essential for establishing maternal immune tolerance to the semi-allogeneic fetus, but the innate immune cells that modulate this process remain poorly defined. Here, we identify CD169+ macrophages in the endometrium as critical regulators of Treg cell recruitment and implantation. These CD169+ macrophages are endometrial localized, exhibit an anti-inflammatory phenotype, and secrete chemokines that attract Treg cells to the endometrium. We also identified CD169+ macrophages in the human endometrium that express chemokines involved in Treg cell recruitment. Our findings identify endometrial CD169+ macrophages as key orchestrators of Treg cell accumulation at the maternal-fetal interface, providing mechanistic insight into implantation and conceptus development.

Pancreatic cancer is associated with a high rate of metastasis and poor prognosis. The formation of a premetastatic niche (PMN) facilitates cancer cell spread and contributes to cancer mortality. Using murine pancreatic cancer models based on expression of oncogenic KRAS in the pancreas epithelium, we discovered that remodeling of the lung microenvironment occurred in mice bearing pancreatic precursor lesions prior to cancer formation. This early-lesion PMN resembled the PMN in cancer-bearing mice, and both feature characteristics of overt metastasis, such as transcriptional reprogramming, activation of fibroblast STAT3 signaling, and infiltration of immunosuppressive arginase 1-positive macrophages. Both patients with pancreatic cancer and mouse models demonstrated elevated serum IL6. Inactivating oncogenic KRAS reduced serum IL6 and reverted fibroblast STAT3 phosphorylation in mouse lungs; loss of lung fibroblast STAT3 phosphorylation was similarly observed when mice were treated with the pan-RAS inhibitor RMC-7977. Whereas arginase 1-positive macrophage infiltration was dispensable for fibroblast STAT3 activation, IL6 blockade inhibited lung fibroblast STAT3 activation. Functionally, fibroblast STAT3 activation was necessary for lung metastasis establishment and growth. Interestingly, activation of STAT3 in the PMN was present in the lungs but not in the liver, in which fibroblast reprogramming occurred only in overt metastasis, pointing to organ-specific PMN formation. In human metastasis samples, phosphorylated STAT3 in fibroblasts was similarly more abundant in the lungs than liver. Together, these data point to organ-specific mechanisms driving formation of the PMN and indicate that reprogramming of the microenvironment prior to metastasis might support early dissemination of pancreatic cancer.