Immune-related adverse events are a major hurdle to the success of immunotherapy. The immunological mechanisms underlying their development and relation to anti-tumour responses are poorly understood. By examining both systemic and tissue-specific immune changes induced by combination anti-CTLA-4 and anti-PD-1 immunotherapy, we found distinct repertoire changes in patients who developed moderate-severe colitis irrespective of their anti-tumour response to therapy. The proportion of circulating monocytes were significantly increased at baseline in patients who subsequently developed colitis compared to patients who did not develop colitis and biopsies from patients with colitis showed monocytic infiltration of both endoscopically and histopathologically normal and inflamed regions of colon. The magnitude of systemic expansion of T cells following commencement of immunotherapy was also greater in patients who developed colitis. Importantly, we show expansion of specific T cell subsets within inflamed regions of the colon, including tissue-resident memory CD8+ T cells and Th1 CD4+ T cells in patients who developed colitis. Our data also suggest that CD8+ T cell expansion was locally induced, while Th1 cell expansion was systemic. Together our data show exaggerated innate and T cell responses to combination immunotherapy synergise to propel colitis in susceptible patients.
Kazi J. Nahar, Felix Marsh-Wakefield, Robert V. Rawson, Tuba N. Gide, Angela L. Ferguson, Ruth O. Allen, Camelia Quek, Ines Pires da Silva, Stephen Tattersall, Christopher J. Kiely, Neomal Sandanayake, Matteo S. Carlino, Geoff McCaughan, James S. Wilmott, Richard A. Scolyer, Georgina V. Long, Alexander M. Menzies, Umaimainthan Palendira
Therapy with radiation plus cisplatin kills HPV+ oropharyngeal squamous cell carcinomas (OPSCCs) by increasing reactive oxygen species beyond cellular antioxidant capacity. To explore why these standard treatments fail for some patients, we evaluated whether the variation in HPV oncoprotein levels among HPV+ OPSCCs affects mitochondrial metabolism, a source of antioxidant capacity. In cell line and patient-derived xenograft models, levels of HPV full-length E6 (fl-E6) inversely correlated with oxidative phosphorylation, antioxidant capacity, and therapy resistance, and fl-E6 was the only HPV oncoprotein to display such correlations. Ectopically expressing fl-E6 in models with low baseline levels reduced mitochondrial mass, depleted antioxidant capacity, and sensitized to therapy. In this setting, fl-E6 repressed the peroxisome proliferator–activated receptor gamma co-activator 1α/estrogen-related receptor α (PGC-1α/ERRα) pathway for mitochondrial biogenesis by reducing p53-dependent PGC-1α transcription. Concordant observations were made in 3 clinical cohorts, where expression of mitochondrial components was higher in tumors of patients with reduced survival. These tumors contained the lowest fl-E6 levels, the highest p53 target gene expression, and an activated PGC-1α/ERRα pathway. Our findings demonstrate that E6 can potentiate treatment responses by depleting mitochondrial antioxidant capacity and provide evidence for low E6 negatively affecting patient survival. E6’s interaction with the PGC-1α/ERRα axis has implications for predicting and targeting treatment resistance in OPSCC.
Malay K. Sannigrahi, Pavithra Rajagopalan, Ling Lai, Xinyi Liu, Varun Sahu, Hiroshi Nakagawa, Jalal B. Jalaly, Robert M. Brody, Iain M. Morgan, Bradford E. Windle, Xiaowei Wang, Phyllis A. Gimotty, Daniel P. Kelly, Elizabeth A. White, Devraj Basu
To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop neurofibromas, benign tumors driven by NF1 loss in Schwann cells (SCs). By comparing normal nerve cells to plexiform neurofibroma (PN) cells using single-cell and bulk RNA sequencing, we identified changes in 5 SC populations, including a de novo SC progenitor–like (SCP-like) population. Long after Nf1 loss, SC populations developed PN-specific expression of Dcn, Postn, and Cd74, with sustained expression of the injury response gene Postn and showed dramatic expansion of immune and stromal cell populations; in corresponding human PNs, the immune and stromal cells comprised 90% of cells. Comparisons between injury-related and tumor monocytes/macrophages support early monocyte recruitment and aberrant macrophage differentiation. Cross-species analysis verified each SC population and unique conserved patterns of predicted cell-cell communication in each SC population. This analysis identified PROS1-AXL, FGF-FGFR, and MIF-CD74 and its effector pathway NF-κB as deregulated in NF1 SC populations, including SCP-like cells predicted to influence other types of SCs, stromal cells, and/or immune cells in mouse and human. These findings highlight remarkable changes in multiple types of SCs and identify therapeutic targets for PN.
Leah J. Kershner, Kwangmin Choi, Jianqiang Wu, Xiyuan Zhang, Melissa Perrino, Nathan Salomonis, Jack F. Shern, Nancy Ratner
Accumulating evidence suggests that high levels of Fusobacterium nucleatum (F. nucleatum) in colorectal tumor tissues can be associated with poor prognosis in patients with colorectal cancer (CRC); however, data regarding distinct prognostic subgroups in F. nucleatum-positive CRC remain limited. Herein, we demonstrated that high iron status was associated with a worse prognosis in CRC patients with F. nucleatum. Patients with CRC presenting elevated serum transferrin saturation exhibited preferential iron deposition in macrophages in the tumor microenvironment. In addition, F. nucleatum induced CCL8 expression in macrophages via the Toll-like receptor 4–nuclear factor-κB (NF-κB) signaling pathway, which was inhibited by iron deficiency. Mechanistically, iron attenuated the inhibitory phosphorylation of NF-κB p65 by activating serine/threonine phosphatases, augmenting tumor-promoting chemokine production in macrophages. Our observations indicate a key role for iron in modulating the NF-κB signaling pathway and suggest its prognostic potential as a determining factor for inter-patient heterogeneity in F. nucleatum-positive CRC.
Taishi Yamane, Yohei Kanamori, Hiroshi Sawayama, Hiromu Yano, Akihiro Nita, Yudai Ohta, Hironori Hinokuma, Ayato Maeda, Akiko Iwai, Takashi Matsumoto, Mayuko Shimoda, Mayumi Niimura, Shingo Usuki, Noriko Yasuda-Yoshihara, Masato Niwa, Yoshifumi Baba, Takatsugu Ishimoto, Yoshihiro Komohara, Tomohiro Sawa, Tasuku Hirayama, Hideo Baba, Toshiro Moroishi
Cancer cells release large quantities of cell-free DNA (cfDNA) into the surrounding tissue and circulation. As cfDNA is a common source of biomarkers for liquid biopsy and has been implicated as a functional mediator for intercellular communication, fundamental characterization of cfDNA topology has widespread biological and clinical ramifications. Whether the topology of cfDNA is such that it exists predominantly in membrane-bound extracellular vesicles (EVs) or in non-vesicular DNA-protein complexes remains poorly understood. Here, we employed a DNA-targeted approach to comprehensively assess total cfDNA topology in cancer. Using preclinical models and patient samples, we demonstrate that nuclear cfDNA is predominantly associated with nucleosomal particles and not EVs, while a substantial subset of mitochondrial cfDNA is membrane-protected and disproportionately derived from non-tumour cells. In addition, discrimination between membrane-protected and accessible mitochondrial cfDNA added diagnostic and prognostic value in a cohort of head and neck cancer patients. Our results support a revised model for cfDNA topology in cancer. Due to its abundance, nuclear cfDNA within nucleosomal particles is the most compelling liquid biopsy substrate, while EV-bound and accessible mitochondrial cfDNA represent distinct reservoirs of potential cancer biomarkers whose structural conformations may also influence their extracellular stability and propensity for uptake by recipient cells.
Ethan Z. Malkin, Steven De Michino, Meghan Lambie, Rita G. Gill, Zhen Zhao, Ariana Rostami, Andrea Arruda, Mark D. Minden, Scott V. Bratman
Malignant melanoma is a major public health issue displaying frequent resistance to targeted therapy and immunotherapy. A major challenge is to better understand how melanoma cells evade immune elimination and how tumor growth and metastasis is facilitated by tumor microenvironment. Here, we show that expression of the cytokine TSLP by epidermal keratinocytes is induced by cutaneous melanoma in both mice and humans. Using genetically engineered models of melanoma and tumor cell grafting combined with TSLP knockout or overexpression, we defined a crosstalk between melanoma cells, keratinocytes and immune cells in establishing a tumor promoting microenvironment. Keratinocyte-derived TSLP is induced by signal(s) derived from melanoma cells and subsequently acts via immune cells to promote melanoma progression and metastasis. Furthermore, we show that TSLP signals through TSLPR-expressing dendritic cells to play an unrecognized role in promoting GATA3+ Tregs expressing a gene signature including ST2, CCR8, ICOS, PD-1, CTLA-4 and OX40 and exhibiting a potent suppressive activity on CD8+ T cell proliferation and IFNγ production. An analogous population of GATA3-expressing Tregs was also identified in human melanoma tumors. Together, our study provides novel insights into the role of TSLP in programming a pro-tumoral immune microenvironment in cutaneous melanoma.
Wenjin Yao, Beatriz German, Dounia Chraa, Antoine Braud, Cecile Hugel, Pierre Meyer, Guillaume Davidson, Patrick Laurette, Gabrielle Mengus, Eric Flatter, Pierre Marschall, Justine Segaud, Marine Guivarch, Pierre Hener, Marie-Christine Birling, Dan Lipsker, Irwin Davidson, Mei Li
It is known that tumor-reactive T cells are initially activated in the draining lymph node, but it is not well known whether and how tumor-infiltrating lymphocytes (TILs) are reactivated in the tumor microenvironment (TME). We hypothesize that defective T cell receptor (TCR) signaling and cosignals in the TME limit T cell reactivation. To address this, we designed a mesenchymal stromal cell–based delivery of local membrane-bound anti-CD3 and/or cosignals to explore their contribution to reactivate T cells inside the TME. Combined anti-CD3 and CD40L rather than CD80 led to superior antitumor efficacy compared with either alone. Mechanistically, TCR activation of preexisting CD8+ T cells synergized with CD40L activation of DCs inside the TME for optimum tumor control. Exogenous TCR signals could better reactivate TILs that then exited to attack distal tumors. This study supplies further evidence that TCR signaling for T cell reactivation in the TME is defective but can be rescued by proper exogenous signals.
Casey Moore, Joonbeom Bae, Longchao Liu, Huiyu Li, Yang-Xin Fu, Jian Qiao
Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal liver cancer with no proven effective systemic therapy. Inhibition of the antiapoptotic protein BCL-XL was found to synergize with a variety of systemic therapies in vitro using cells dissociated from patient-derived xenografts (PDX) of FLC or cells dissociated directly from surgical patient resections. As BCL-XL is physiologically expressed in platelets, prior efforts to leverage this vulnerability in other cancers have been hampered by severe thrombocytopenia. To overcome this toxicity, we treated FLC models with DT2216, a proteolysis targeting chimera (PROTAC) that directs BCL-XL for degradation via the von Hippel-Lindau (VHL) E3 ligase, which is minimally expressed in platelets. The combination of irinotecan and DT2216 in vitro on cells directly acquired from patients or in vivo using several xenografts derived from patients with FLC demonstrated remarkable synergy and at clinically achievable doses not associated with significant thrombocytopenia.
Bassem Shebl, Denise Ng, Gadi Lalazar, Carly Rosemore, Tova M. Finkelstein, Rachael D. Migler, Guangrong Zheng, Peiyi Zhang, Caroline S. Jiang, Adam Qureshi, Roger Vaughan, Mark Yarchoan, Ype P. de Jong, Charles M. Rice, Philip Coffino, Michael V. Ortiz, Daohong Zhou, Sanford M. Simon
Osteosarcoma (OS) is a lethal disease with few known targeted therapies. Here, we show that decreased ATRX expression is associated with more aggressive tumor cell phenotypes, including increased growth, migration, invasion, and metastasis. These phenotypic changes correspond with activation of NF-κB signaling, extracellular matrix remodeling, increased integrin αvβ3 expression, and ETS family transcription factor binding. Here, we characterize these changes in vitro, in vivo, and in a data set of human OS patients. This increased aggression substantially sensitizes ATRX-deficient OS cells to integrin signaling inhibition. Thus, ATRX plays an important tumor-suppression role in OS, and loss of function of this gene may underlie new therapeutic vulnerabilities. The relationship between ATRX expression and integrin binding, NF-κB activation, and ETS family transcription factor binding has not been described in previous studies and may impact the pathophysiology of other diseases with ATRX loss, including other cancers and the ATR-X α thalassemia intellectual disability syndrome.
Suzanne Bartholf DeWitt, Sarah Hoskinson Plumlee, Hailey E. Brighton, Dharshan Sivaraj, E.J. Martz, Maryam Zand, Vardhman Kumar, Maya U. Sheth, Warren Floyd, Jacob V. Spruance, Nathan Hawkey, Shyni Varghese, Jianhua Ruan, David G. Kirsch, Jason A. Somarelli, Ben Alman, William C. Eward
The histone methyltransferase PRC2 plays a complex role in cancer. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with frequent loss-of-function mutations in PRC2 that are associated with poor outcome. Here, we identify a critical role for PRC2 loss in driving MPNST metastasis. PRC2-dependent metastatic phenotypes include increased collagen-dependent invasion, upregulation of matrix remodeling enzymes, and elevated lung metastasis in orthotopic mouse models. Furthermore, clinical sample analysis determines that PRC2 loss correlates with metastatic disease, increased fibrosis, and decreased survival in MPNST patients. These results may have broad implications for PRC2 function across multiple cancers and provide a strong rationale for investigating potential therapies targeting ECM remodeling enzymes and tumor fibrosis to improve outcomes in MPNST patients.
Qierra R. Brockman, Amanda Scherer, Gavin R. McGivney, Wade R. Gutierrez, Andrew P. Voigt, Alexandra L. Isaacson, Emily A. Laverty, Grace Roughton, Vickie Knepper-Adrian, Benjamin Darbro, Munir R. Tanas, Christopher S. Stipp, Rebecca D. Dodd
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