Oncology
Abstract
Few effective therapeutic options exist following progression on immune checkpoint blockade (ICB) for melanoma. Here we utilize a platform incorporating transcriptomic profiling, high-throughput drug screening (HTDS) and murine models to demonstrate the pre-clinical efficacy of several combinatorial regimens against ICB-resistant melanoma. Transcriptomic analysis of ICB-resistant melanomas demonstrated activation of several targetable pathways. HTDS targeting these pathways identified several effective combinations in ICB-resistant patient-derived xenograft models. The combination of cobimetinib and regorafenib (termed Cobi+Reg) emerged as a particularly promising regimen, with efficacy against distinct molecular melanoma subtypes and following progression on ICB in immunocompetent models. Transcriptomic and spatial analysis of Cobi+Reg-treated tumors demonstrated upregulation of antigen presentation machinery, with concomitantly increased activated T cell infiltration. Combining Cobi+Reg with ICB was superior to either modality in vivo. This analytical platform exploits the biology of ICB-resistant melanoma to identify therapeutic vulnerabilities, resulting in the identification of drug combinations that form the basis for rational clinical trial design in the setting of advanced melanoma resistant to ICB.
Authors
Imran Khan, Aida Rodriguez-Brotons, Anukana Bhattacharjee, Vladimir Bezrookove, Altaf Dar, David De Semir, Mehdi Nosrati, Ryan Ice, Liliana Soroceanu, Stanley P. Leong, Kevin B. Kim, Yihui Shi, James E. Cleaver, James R. Miller, Pierre-Yves Desprez, John M. Kirkwood, Marcus Bosenberg, Nathan Salomonis, Sean McAllister, Mohammed Kashani-Sabet
Abstract
Downregulation of antigen presentation and lack of immune infiltration are defining features of small cell lung cancer (SCLC) limiting response to immune checkpoint blockade (ICB). While a high MHC Class I, immune-inflamed subset benefits from ICB, underlying mechanisms of immune response in SCLC have yet to be elucidated. Here we show that in the landmark IMpower133 clinical trial high, but not low, NOTCH1 expression is significantly associated with longer survival with the addition of ICB to chemotherapy among ~80% of SCLC patients with neuroendocrine-enriched tumors (ASCL1-enriched, HR 0.39, P = 0.0012; NEUROD1-enriched, HR 0.44, P = 0.024). Overexpression or pharmacologic activation of NOTCH1 in ASCL1 and NEUROD1 SCLC cell lines dramatically upregulates MHC Class I through epigenetic reactivation of STING. In syngeneic mouse models, Notch1 activation reprograms SCLC tumors from immune-excluded to immune-inflamed, facilitating durable, complete responses with ICB combined with a STING agonist. STING1 expression is significantly enriched in high compared to low NOTCH1 expressing tumors in IMpower133 thereby validating our proposed mechanism. Our data reveal a previously undiscovered role for NOTCH1 as a critical driver of SCLC immunogenicity and a potential predictive biomarker for ICB in SCLC. NOTCH1 activation may be a therapeutic strategy to unleash anti-tumor immune responses in SCLC and other neuroendocrine cancers in which NOTCH1 is typically suppressed.
Authors
Yoo Sun Kim, Barzin Y. Nabet, Briana N. Cortez, Nai-Yun Sun, Robin Sebastian, Christophe E. Redon, Anagh Ray, Liang Liu, Afeez A. Ishola, Sarah Loew, Anjali Dhall, Sivasish Sindiri, Velimir Gayevskiy, Min-Jung Lee, Shraddha Rastogi, Nahoko Sato, Noemi Kedei, Thorkell Andresson, Sudipto Das, Suresh Kumar, Alan E. Bers, Hongliang Zhang, Alberto Chiappori, Priyanka Gopal, Mohamed E. Abazeed, Haobin Chen, Mirit I. Aladjem, Yves Pommier, Moises J. Velez, David S. Shames, Nitin Roper
Abstract
Gain of plasticity and loss of MHC-II enable tumor cells to evade immune surveillance contributing to tumor development. Here, we showed that the transcriptional corepressor RCOR2 is a key factor that integrates two epigenetic programs surveilling tumor plasticity and immunogenicity. RCOR2 was upregulated predominantly in tumor cells and promoted tumor development in mice through reducing tumor cell death by CD4+/CD8+ T cells and inducing cancer stemness. Mechanistically, RCOR2 repressed RNF43 expression through LSD1-mediated demethylation of histone H3 at lysine 4 to induce activation of Wnt/β-catenin and tumor stemness. Simultaneously, RCOR2 inhibited CIITA expression through HDAC1/2-mediated deacetylation of histone H4 at lysine 16, leading to MHC-II silencing in tumor cells and subsequent impairment of CD4+/CD8+ T cell immunosurveillance, thereby promoting immune evasion. RCOR2 loss potentiated anti-PD-1 therapy in mouse models of cancer and correlated with better response to anti-PD-1 therapy in human patients. Collectively, these findings uncover a “two birds with one stone” effect for RCOR2, highlighting its potential as a valuable target for improved cancer therapy.
Authors
Lei Bao, Ming Zhu, Maowu Luo, Ashwani Kumar, Yan Peng, Chao Xing, Yingfei Wang, Weibo Luo
Abstract
Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of metastatic TNBC. Further study demonstrated that MTAP deficiency or inhibition rendered TNBC susceptibility to chemotherapeutic agents, particularly PARPi. Mechanistically, targeting MTAP that synergized with PARPi by disrupting the METTL16-MAT2A axis involved in methionine metabolism and depleting in vivo s-adenosylmethionine (SAM) levels. Exhausted SAM in turn impaired PARPi-induced DNA damage repair through attenuation of MRE11 recruitment and end resection by diminishing MRE11 methylation. Notably, brain metastatic TNBC markedly benefited from a lower dose of PARPi and MTAP deficiency/inhibition synergy due to the inherently limited methionine environment in the brain. Collectively, our findings revealed a feed-forward loop between methionine metabolism and DNA repair through SAM, highlighting a therapeutic strategy of PARPi combined with MTAP deficiency/inhibition for TNBC.
Authors
Xiangyu Zeng, Fei Zhao, Xinyi Tu, Yong Zhang, Wen Yang, Jing Hou, Qi Jiang, Shouhai Zhu, Zheming Wu, Yalan Hao, Lingxin Zhang, Richard M. Weinshilboum, Kaixiong Tao, Liewei Wang, Zhenkun Lou
Abstract
In preclinical mouse models of triple-negative breast cancer (TNBC), we show that a combination of chemotherapy with cisplatin (CDDP) and eribulin (Eri) was additive from an immunological point of view and was accompanied by the induction of an intratumoral immune and inflammatory response favored by the immunogenic cell death induced by CDDP, as well as by the vascular and tumor stromal remodeling induced by each chemotherapy. Unexpectedly, despite the favorable immune context created by this immunomodulatory chemotherapy combination, our models remained refractory to the addition of anti–PD-L1 immunotherapy. These surprising observations led us to discover that CDDP chemotherapy was simultaneously responsible for the production of TGF-β by several populations of cells present in tumors, which favored the emergence of different subpopulations of immune cells and cancer-associated fibroblasts characterized by immunosuppressive properties. Accordingly, co-treatment with anti–TGF-β restored the immunological synergy between this immunogenic doublet of chemotherapy and anti–PD-L1 in a CD8-dependent manner. Translational studies revealed the unfavorable prognostic effect of the TGF-β pathway on the immune response in human TNBC, as well as the ability of CDDP to induce this cytokine also in human TNBC cell lines, thus highlighting the clinical relevance of targeting TGF-β in the context of human TNBC treated with chemoimmunotherapy.
Authors
Laura Kalfeist, Fanny Ledys, Stacy Petit, Cyriane Poirrier, Samia Kada Mohammed, Loïck Galland, Valentin Derangère, Alis Ilie, David Rageot, Romain Aucagne, Pierre-Simon Bellaye, Caroline Truntzer, Marion Thibaudin, Mickaël Rialland, François Ghiringhelli, Emeric Limagne, Sylvain Ladoire
Abstract
Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME) and dampen the immune response, negatively affecting patient survival. Therefore, targeting TAMs could address the limitations of current cancer treatments. However, drug development in this area remains limited. The Leukocyte-associated Immunoglobulin-like Receptor-1 (LAIR1), also called CD305, is prominently expressed on the surface of TAMs. We have uncovered a previously unrecognized immunosuppressive LAIR1 → Factor XIII A (FXIII-A) → Collagen IV pathway across various cancer types. Inhibition of LAIR1, either through knockout (Lair1–/–), antibody blockade (aLAIR1), or a chimeric antigen receptor (CAR) design (3-in-1 CAR by combining tumor targeting, T cell trafficking, and remodeling of the immunosuppressive TME in one CAR construct) provides enhanced antitumor response. LAIR1 inhibition enhances peripheral and intratumoral CD8 memory T-cell populations, induces a phenotypic shift of M2-like Macrophages towards M1, and normalizes tumor collagen IV and structural components in the TME, facilitating effective tumor-T cell interactions and tumor suppression. Enhanced antitumor responses were observed when Lair1–/– or aLAIR1 was used alone or combined with CAR T cells or when the 3-in-1 CAR T cells were used solely in chemotherapy-radiation-PD-1 blockade-resistant tumor models. These findings position LAIR1 inhibition as a promising strategy for cancer immunotherapies.
Authors
Haipeng Tao, Dongjiang Chen, Changlin Yang, Duy T. Nguyen, Georges Abboud, Ruixuan Liu, Tianyi Liu, Avirup Chakraborty, Alicia Y. Hou, Nicole A. Petit, Muhammad Abbas, Robert W. Davis, Janie Zhang, Christina Von Roemeling, Mohammed O. Gbadamosi, Linchun Jin, Tongjun Gu, Tuo Lin, Pengchen Wang, Alfonso Pepe, Diego Ivan Pedro, Hector R. Mendez-Gomez, Chao Xie, Aida Karachi, Frances Weidert, Dan Jin, Chenggang Wang, Kaytora Long-James, Elizabeth K. Molchan, Paul Castillo, John A. Ligon, Ashley P. Ghiaseddin, Elias J. Sayour, Maryam Rahman, Loic P. Deleyrolle, Betty Y.S. Kim, Duane A. Mitchell, W. Gregory Sawyer, Jianping Huang
Abstract
A subgroup (~20-30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, while AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi.
Authors
Shipra Shukla, Dan Li, Woo Hyun Cho, Dana M. Schoeps, Holly M. Nguyen, Jennifer L. Conner, Marjorie L. Roskes, Anisha Tehim, Gabriella Bayshtok, Mohini R. Pachai, Juan Yan, Nicholas A. Teri, Eric Campeau, Sarah Attwell, Patrick Trojer, Irina Ostrovnaya, Anuradha Gopalan, Ekta Khurana, Eva Corey, Ping Chi, Yu Chen
Abstract
Since the lung is a mucosal barrier organ with a unique immunologic environment, mechanisms of immunoregulation in lung cancer may differ from those of other malignancies. Consistent with this notion, we found that CD8+ T cells play a paradoxical role in facilitating, rather than ameliorating, the growth of multiple lung adenocarcinoma models. These include spontaneous, carcinogen-induced, and transplantable tumor cell line models. Specifically, we found that CD8+ T cells promote homing of CD4+Foxp3+ T regulatory cells to the tumor bed by increasing levels of CCR5 chemokines in the tumor microenvironment in an IFN-γ and TNF-α dependent manner. Contrary to their canonical role, these Th1 cytokines contributed to accelerated growth of murine lung adenocarcinomas while suppressing the growth of other malignancies. Surprisingly, lung cancer cells themselves can serve as a dominant source of IFN-γ, and deletion of this cytokine from cancer cells using CRISPR/Cas-9 decreases tumor growth. Importantly for translational applications, a high level of IFN-γ was also found in human lung cancer patients at both the mRNA and protein level. Our data outlines what we deem a novel and previously undefined lung cancer specific immunoregulatory pathway that may be harnessed to tailor immune based therapy specifically for this malignancy.
Authors
Christina Kratzmeier, Mojtaba Taheri, Zhongcheng Mei, Isabelle Lim, May A. Khalil, Brandon Carter-Cooper, Rachel E. Fanaroff, Chin S. Ong, Eric B. Schneider, Stephanie Chang, Erica Leyder, Dongge Li, Irina G. Luzina, Anirban Banerjee, Alexander Sasha Krupnick
Abstract
BACKGROUND. Axicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent B-cell lymphomas in the ZUMA-5 trial. METHODS. Here, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 follicular lymphoma (FL) patients. RESULTS. In univariate and multivariate analyses, pre-treatment inflammatory markers, including TNFα and IL12p40, as well as total metabolic tumor volume (TMTV) associated with disease progression. Conversely, T-naïve-like product phenotype associated with improved outcome, particularly in high TMTV patients. These covariates improved risk stratification when combined with the FL International Prognostic Index. Post-infusion, CAR T-cell expansion associated with improved outcome, while serum inflammatory and immuno-modulatory markers, including TNFα associated with disease progression and occurrence of high-grade cytokine release syndrome or neurologic events, presenting targets to improve the therapeutic index of axi-cel in FL. Tumor gene expression profiling revealed that both type I and II IFN signaling associated with disease progression and higher expression of T cell exhaustion markers, including TIM3 and LAG3. Pre- or post-treatment CD19 expression on tumor was not associated with outcome. CONCLUSION. These findings offer insights into mechanisms of resistance and toxicity, risk stratification, and strategies for development of next generation CAR-T approaches. TRIAL REGISTRATION. ClinicalTrials.gov NCT03105336. FUNDING. Kite, a Gilead Company.
Authors
Soumya Poddar, Jiali Yan, Gayatri Tiwari, Darawan Rinchai, Justin Budka, Wangshu Zhang, Weixin Peng, Shruti Salunkhe, Madison Davis, Qinghua Song, Sara Beygi, Harry Miao, Mike Mattie, Rhine S. Shen, Caron A. Jacobson, Davide Bedognetti, Simone Filosto, Sattva S. Neelapu
Abstract
Authors
Caitlin M. Stewart, Sonya Parpart-Li, James R. White, Mitesh Patel, Oliver Artz, Michael B. Foote, Erika Gedvilaite, Michelle F. Lamendola-Essel, Drew Gerber, Rohini Bhattacharya, Justin M. Haseltine, Kety Huberman, Kelly L. Bolton, Ross L. Levine, Luis A. Diaz, Jr.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)