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Highlights d Endogenous glucocorticoid signaling shapes CD8 + T cell differentiation in tumors d The glucocorticoid receptor transactivates IL-10 and checkpoint receptor expression d Tumor monocyte-macrophage lineage cells produce glucocorticoid d Glucocorticoid signaling in CD8 + T cells reduces immune checkpoint blockade efficacy

Breast-conserving surgery with adjuvant radiation therapy has become the standard of care for women with early stage breast cancer, and as a result, a large number of patients are affected by the cutaneous sequelae of radiation therapy. These dermatologic toxicities may present during treatment or years later and can significantly impact patients’ quality of life. In this review, we discuss the clinical presentation, prevention, and management of radiation-induced cutaneous toxicities in women with breast cancer, including radiation dermatitis, radiation recall, radiation-induced morphea, radiation-induced fibrosis, and cutaneous malignancies in irradiated skin.

As advances in cancer therapies have improved cancer-related survival, novel therapeutics have also introduced a variety of dermatologic toxicities, and an increased number of patients are living with these sequalae. Women with cancer in particular experience a spectrum of dermatologic conditions that affect their skin, hair, nail, and mucosal surfaces. Studies have shown that these toxic effects can significantly affect quality of life and alter a woman’s self-image, cultural identity, femininity, sexuality, and mental health. In severe instances, dermatologic toxicities may even disrupt cancer therapy and can therefore affect overall survival and treatment response. In this article, we review the dermatologic adverse effects from traditional chemotherapy, targeted therapy, immune checkpoint inhibitors, and endocrine therapy that disproportionately affect women. The timely diagnosis and management of these dermatologic conditions is crucial in the multidisciplinary care of women with cancer.

The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome–heat shock protein 70 (HSP70) signaling axis is triggered by CD8 + T cell cytotoxicity and contributes to the development of adaptive resistance to anti–programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti–PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti–PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti–PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti–PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.

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e14114 Background: Checkpoint inhibitors such as anti-PD1 (aPD1) have revolutionized treatment of metastatic melanoma. However, a large subset of patients receiving such treatment fails to respond to aPD1 monotherapy due to mechanisms such as PD-L1 upregulation within the tumor and T cell exhaustion in the tumor microenvironment. The PGE2/COX2 signaling pathway is one of the pathways implicated in T cell exhaustion and PD1/PD-L1 upregulation and thus represents an attractive pharmacologic target to enhance effects of aPD1 therapy due to the availability and safety of inhibitors such as aspirin or NSAIDs. There is evidence that PGE2/COX2 pathway inhibitors act synergistically with aPD1 therapy in murine melanoma and breast cancer models. Here we aimed to further characterize this synergism using the YUMMER (Yale University Mouse Melanoma Exposed to Radiation) 1.7 model, an irradiated, syngeneic cell line originating from BrafV600E; Pten-/-; and Cdkn2a -/- genetically engineered mouse melanomas. YUMMER1.7 cells implanted into the flanks of C57BL6/j mice show reproducible but partial responses to intraperitoneal aPD1 therapy and thus serves as an ideal platform to study whether concurrent PGE2/COX2 pathway blockade may result in additive effects to aPD1 therapy. Methods: 6-7 week old male C57BL6/j mice (n = 20) were injected with 500K YUMMER1.7 cells and treated with aPD1 therapy alone starting on day 7 after tumor implantation (n = 10) or with aPD1 therapy starting on day 7 in addition to ibuprofen dissolved in drinking water at a concentration of 1 mg/mL started on the day of tumor implantation (n = 10). Using an average daily water consumption estimate of 6 mL/day, this translates to a human equivalent of roughly 1200 mg/day, a moderate dose of ibuprofen. Tumor growth was monitored and tracked to an endpoint of 1cm3. Results: Tumor volume at day 17 significantly differed between the two groups (p < 0.0001). Survival curves were significantly different between the two groups (p < 0.0001); all tumors treated with aPD1 alone grew to endpoint by day 32, while all tumors treated with aPD1 + ibuprofen regressed with 8 out of 10 showing complete regression by day 32. Conclusions: We have shown that ibuprofen strongly synergizes with aPD1 therapy in a murine model of melanoma, complementing existing evidence. This suggests that PGE2/COX2 inhibitors such as NSAIDs, which are over-the-counter agents with a well-studied safety profile, may serve as a promising means of enhancing the response to aPD1 therapies such as nivolumab in melanoma patients who initially fail aPD1 monotherapy.

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