Abstract
Immune checkpoint blockade (ICB) therapy has improved patient survival in a variety of cancers, but its resistance presents a major clinical challenge. It remains unclear whether therapeutic ...resistance is driven predominantly by refractory clones of cancer cells or by immunosuppressive microenvironment. To address this, we utilized syngeneic transplantation model and performed clonal tracing of cancer cells to monitor the response to ICB. Different cancer clones displayed variable sensitivity to ICB treatment, reflecting intratumoral heterogeneity in therapy response. Furthermore, different recipients manifested distinct resistance mechanisms. ICB-responders developed resistance through selection and expansion of pre-existing ICB-resistant cancer clones, whereas non-responders presented with irresponsive microenvironment rather than dominance of resistant cancer clones. Extrapolation of the tumor-infiltrating immune repertoire revealed that higher IgG and lower IgA strongly correlated with better ICB response. This biomarker was further validated in multiple clinical cohorts. Our approach discriminates different sources of resistance to ICB, and identifies humoral immunity as biomarker of ICB response.
Citation Format: Shengqing Gu, Xihao Hu, Xiaoqing Wang, Peng Jiang, Ziyi Li, Nicole Traugh, Xia Bu, Xiaofang Xing, Gordon J. Freeman, Myles Brown, Xiaole S. Liu. Clonal tracing reveals different mechanisms of resistance to immune checkpoint blockade abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3779.
Abstract
Despite remarkable clinical efficacies of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits in triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo ...CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that inhibition of the E3 ubiquitin ligase COP1 in cancer cells decreases the secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances tumor immunity and ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed COP1 functions through proteasomal degradation of the C/ebpδ protein. COP1 substrate TRIB2 functions as a scaffold linking COP1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. COP1 inhibition stabilizes C/ebpδ to suppress the expression of macrophage chemoattractant genes. Our integrated approach implicates COP1 as a target for improving cancer immunotherapy efficacy by regulating chemokine secretion and macrophage infiltration in the TNBC tumor microenvironment.
Citation Format: Xiaoqing Wang, Collin Tokheim, Shengqing S. Gu, Binbin Wang, Qin Tang, Yihao Li, Nicole Traugh, Zexian Zeng, Yi Zhang, Boning Zhang, Jingxin Fu, Tengfei Xiao, Wei Li, Clifford Meyer, Peng Jiang, Paloma Cejas, Klothilda Lim, Henry Long, Myles Brown, X. Shirley Liu. In vivo CRISPR screens identify E3 ligase COP1 as a modulator of macrophage infiltration and cancer immunotherapy target abstract. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P108.
Abstract
Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR ...screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a critical suppressor of the NF-κB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified SMAC mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T-cell-dependent killing, and synergizes with ICB. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.
Citation Format: Shengqing Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Nicole Traugh, Ziyi Li, Clifford Meyer, Blair Stewig, Yingtian Xie, Xia Bu, Michael Manos, Alba Font-Tello, Evisa Gjini, Ana Lako, Klothilda Lim, Jake Conway, Alok Tewari, Zexian Zeng, Avinash Das Sahu, Collin Tokheim, Jason L. Weirather, Jingxin Fu, Yi Zhang, Benjamin Kroger, Jin Hua Liang, Paloma Cejas, Gordon J. Freeman, Scott J. Rodig, Henry Long, Benjamin E. Gewurz, F. Stephen Hodi, Myles Brown, X. Shirley Liu. Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 65.
Abstract
Immune checkpoint blockade (ICB) therapy has dramatically improved the prognosis of several types of cancer. However, only a small proportion of patients respond. Although multiple ...biomarkers/mechanisms of resistance to ICB have been identified, it remains elusive to what extent the cellular/molecular mechanisms contribute to the heterogeneity of ICB response. To this end, we applied clonal barcoding for lineage tracing of cancer cells following control IgG or ICB treatment in a transplantation mouse model. We identified significant clonal heterogeneity within cancer cells in response to ICB, suggestive of a minority of pre-existing ICB-resistant clones prior to treatment. Furthermore, counter-intuitively, ICB-responding tumors harbored a higher proportion of ICB-resistant clones than nonresponding tumors post-treatment, indicating that the tumor microenvironment might dictate the initial response to ICB. Integrated gene expression and immune repertoire analyses of the tumor microenvironment identified more T-cell and B cell infiltration in the ICB responders, and found that BCR class switch is associated with ICB response. Our study established a system to assess the contributions of cancer cell-intrinsic and microenvironmental factors in response to ICB treatment, and identified B cell infiltration and repertoire constitution as a novel biomarker for ICB response.
Citation Format: Shengquing Stan Gu, Xihao Sherlock Hu, Xiaoqing Shawn Wang, Ziyi Li, Nicole Traugh, Xia Bu, Xiaofang Xing, Gordon Freeman, Myles Brown, Xiaole Shirley Liu. Microenvironmental factors shape resistance patterns to immune checkpoint blockade abstract. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A077.
Abstract
Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients responds to treatment. To predict ICB response we developed ...TIDE, a computational method to model two primary mechanisms of tumor immune evasion: inducing T-cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and preventing T-cell infiltration in tumors with low CTL level. We identified signatures of T-cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T-cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research. TIDE source code and a web application are available at http://tide.dfci.harvard.edu.
Citation Format: Peng Jiang, Shengqing Gu, Deng Pan, Jingxin Fu, Avinash Sahu, Xihao Hu, Ziyi Li, Nicole Traugh, Xia Bu, Bo Li, Jun Liu, Gordon J Freeman, Myles A Brown, Kai W. Wucherpfennig, Xiaole Shirley Liu. Signatures of T-cell dysfunction and exclusion predict cancer immunotherapy response abstract. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B077.
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